Miracle-dz/UniFAR-FTUs huggingface dataset:
Induction of Hepatitis C Virus E1 Envelope Protein-Specific Immune Response Can Be Enhanced by Mutation of N-Glycosylation Sites

ABSTRACT Deglycosylation of viral glycoproteins has been shown to influence the number of available epitopes and to modulate immune recognition of antigens. We investigated the role played by N-glycans in the immunogenicity of hepatitis C virus (HCV) E1 envelope glycoprotein, a naturally poor immunogen. Eight plasmids were engineered, encoding E1 protein mutants in which the four N-linked glycosylation sites of the protein were mutated separately or in combination. In vitro expression studies showed an influence of N-linked glycosylation on expression efficiency, instability, and/or secretion of the mutated proteins. Immunogenicity of the E1 mutants was studied in BALB/c mice following intramuscular and intraepidermal injection of the plasmids. Whereas some mutations had no or only minor effects on the antibody titers induced, mutation of the fourth glycosylation site (N4) significantly enhanced the anti-E1 humoral response in terms of both seroconversion rates and antibody titers. Moreover, antibody induced by the N4 mutant was able to recognize HCV-like particles with higher titers than those induced by the wild-type construct. Epitope mapping indicated that the E1 mutant antigens induced antibody directed at two major domains: one, located at amino acids (aa) 313 to 332, which is known to be reactive with sera from HCV patients, and a second one, located in the N-terminal domain of E1 (aa 192 to 226). Analysis of the induced immune cellular response confirmed the induction of gamma interferon-producing cells by all mutants, albeit to different levels. These results show that N-linked glycosylation can limit the antibody response to the HCV E1 protein and reveal a potential vaccine candidate with enhanced immunogenicity.
Factors contributing to stroke in patients with atherosclerotic disease of the great vessels: the role of diabetes.

The incidence of carotid artery disease and cerebrovascular symptoms were determined in 102 consecutive patients with peripheral arterial disease. Symptoms were correlated with risk factors of age, hypertension, smoking and diabetes and with the extent of disease at the carotid bifurcation. The incidence of stroke with permanent neurological deficit was twice as high in diabetics as in non-diabetics with equivalent atherosclerotic vascular disease (p less than .05). In women, the incidence of stroke was three times higher in diabetics (p less than .02). The number of transient ischemic attacks was significantly higher in non-diabetics (p less than .02). The total number of ischemic episodes in diabetics and non-diabetics was equivalent. This indicates that diabetics are more prone to irreversible destruction of ischemic brain tissue regardless of the nature of the circulatory disturbance.
Robust lane detection based on gradient direction

A robust and effective method to detect lane in the images captured with a vehicle-mounted monocular camera in challenging environments is proposed in this paper. In the newly proposed approach, the gradient direction (GD) feature and the lane boundaries projection model are used. Using GD feature and GD Gaussian distribution with the likelihood function, the lane detection is performed by employing maximum a posteriori (MAP) estimation with prior knowledge. Afterwards, the model parameter values are estimated, with which the lane geometric structure (such as the lane curvature and change rate), the host vehicle position and heading direction in the lane can be also calculated. The experimental results show that the method works more robustly and accurately in various situations with the broken and worn lane markings, the curved lane, the messy shadows, the sun glare, the occlusion of other vehicles, the dusky light in the evening, etc.
Shearing Melt Out of the Earth: An Experimentalist's Perspective on the Influence of Deformation on Melt Extraction

Melt extraction from the Earth's mantle requires some form of channelized flow to produce the observed disequilibrium between the crust-forming lavas and their mantle sources. In this review, we discuss the influence of deformation on melt-extraction processes, with an emphasis on the understanding gained from a wide range of laboratory experimental investigations. Rheological properties of partially molten rocks are very sensitive to melt distribution, and melt distribution is profoundly influenced by deviatoric stress in a viscously deforming partially molten rock, establishing a coupling between deformation and melt distribution. During deformation, this coupling can lead to organization of melt into melt-enriched shear zones at length scales longer than the grain size. We discuss the current state of understanding of this process, with some speculation on its role in the ensemble of processes that constitute melt extraction from the Earth.
Mutational Analysis of the N-Terminal Domain of Moloney Murine Leukemia Virus Capsid Protein

ABSTRACT Retroviral capsid (CA) proteins contain a structurally conserved N-terminal domain (NTD) consisting of a β-hairpin and six to seven α-helices. To examine the role of this domain in Moloney murine leukemia virus (MoMLV) replication, we analyzed 18 insertional mutations in this region. All mutants were noninfectious. Based on the results of this analysis and our previous studies on additional mutations in this domain, we were able to divide the NTD of MoMLV CA into three functional regions. The first functional region included the region near the N terminus that forms the β-hairpin and was shown to control normal maturation of virions. The second region included the helix 4/5 loop and was essential for the formation of spherical cores. The third region encompassed most of the NTD except for the above loop. Mutants of this region assembled imperfect cores, as seen by detailed electron microscopy analyses, yet the resulting particles were efficiently released from cells. The mutants were defective at a stage immediately following entry of the core into cells. Despite possessing functional reverse transcriptase machinery, these mutant virions did not initiate reverse transcription in cells. This block could be due to structural defects in the assembling core or failure of an essential host protein to interact with the mutant CA protein, both of which may prevent correct disassembly upon entry of the virus into cells. Future studies are needed to understand the mechanism of these blocks and to target these regions pharmacologically to inhibit retroviral infection at additional stages.
Subclinical variations on ECG and their associations with structural brain aging networks

Impaired cardiac function is associated with cognitive impairment and brain imaging features of aging. Cardiac arrhythmias, including atrial fibrillation, are implicated in clinical and subclinical brain injuries. Even in the absence of a clinical diagnosis, subclinical or prodromal substrates of arrhythmias, including an abnormally long or short P-wave duration (PWD), a measure associated with atrial abnormalities, have been associated with stroke and cognitive decline. However, the extent to which PWD has subclinical influences on overall aging patterns of the brain is not clearly understood. Here, using neuroimaging and ECG data from the UK Biobank, we use a novel regional "brain age" method to identify the brain aging networks associated with abnormal PWD. We find that PWD is inversely associated with accelerated brain aging in the sensorimotor, frontoparietal, ventral attention, and dorsal attention networks, even in the absence of overt cardiac diseases. These findings suggest that detrimental aging outcomes may result from subclinically abnormal PWD.
Prevalence and factors associated with short birth interval in Kaya Municipality, North Central Burkina Faso: a multilevel Poisson regression modeling with a robust variance of a community survey

A short birth interval adversely affects the health of mothers and children. This study aimed to measure the prevalence of short birth intervals and identify their associated factors in a semi-urban setting in Burkina Faso. We conducted a cross-sectional study in which data were collected in households between May and October 2022. The dependent variable was the short birth interval (SBI), defined by the World Health Organization as the time between two live births. We performed a multilevel mixed-effects Poisson regression with robust variance to determine the factors associated with the SBI by reporting adjusted prevalence ratios (aPR) with a 95% confidence interval (CI). A total of 5544 birth intervals were recorded from 4067 women. A short birth interval was found in 1503 cases out of 5544, i.e., a frequency of 27.1%. The prevalence of short birth interval (time between two live births less than 33 months) was higher in never users of modern contraceptive users (aPR=1.24; 95% CI [1.14-1.34] vs. previous users), in younger ages with aPR of 4.21 (95% CI [3.30-5.37]), 2.47 (95% CI [1.96-3.11]), and 1.45 (95% CI [1.16-1.81]), respectively for under 18, 18-24 years old, and 25-34 years old, compared to 35 and over. Childbirths occurring before the implementation of the maternal and infant free health care policy (aPR=2.13; 95% CI [1.98-2.30]) and also before the free FP policy (aPR=1.53; 95% CI [1.28-1.81]) were found also protective against SBI. Women with low socio-economic positions were more likely to have SBI. This study found a high SBI in Burkina Faso (more than one woman out of four). Our results have programmatic implications, as some factors, such as contraceptive practice and socioeconomic status, are modifiable. These factors need particular attention to lengthen birth intervals and, in turn, improve mother-child couple health by reducing short birth interval consequences.
Control of human pancreatic beta cell kinome by GLP-1R biased agonism

Aim To determine the kinase activity profiles of human pancreatic beta cells downstream of GLP-1R balanced versus biased agonist stimulations. Materials and methods This study analysed the kinomic profiles of human EndoC-βh1 cells following vehicle and glucagon-like peptide-1 receptor (GLP-1R) stimulation with the pharmacological agonist exendin-4, as well as exendin-4-based biased derivatives exendin-phe1 and exendin-asp3 for acute (10-minute) versus sustained (120-minute) responses, using PamChip® protein tyrosine kinase (PTK) and serine/threonine kinase (STK) assays. The raw data were filtered and normalised using BioNavigator. The kinase analyses were conducted with R, mainly including kinase-substrate mapping and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Results The present analysis reveals that kinomic responses are distinct for acute versus sustained GLP-1R agonist (GLP-1RA) exposure, with individual responses associated with agonists presenting specific bias profiles. According to pathway analysis, several kinases, including JNKs, PKCs, INSR and LKB1, are important GLP-1R signalling mediators, constituting potential targets for further research on biased GLP-1R downstream signalling. Conclusion Results from this study suggest that differentially biased exendin-phe1 and exendin-asp3 can modulate distinct kinase interaction networks. Further understanding of these mechanisms will have important implications for the selection of appropriate anti-T2D therapies with optimised downstream kinomic profiles.
Comparative Study of Global MHD Simulations of the Terrestrial Magnetosphere With Different Numerical Schemes

We compare recent global MHD simulation models of the terrestrial magnetosphere based on different numerical schemes. The schemes include the finite-difference method based on the modified leapfrog (MLF) scheme, and the semi-Lagrangian scheme based on the constrained interpolation profile (CIP) algorithm. With the two models, we examined the simulation under a northward interplanetary magnetic field (IMF) condition. As a result, we found out that the two simulation models give consistent results on the magnetopause locations at the subsolar point and the terminator, and the overall structures of the cusp in the meridian plane. However, discrepancies are also found in the location and jump conditions of the bow shock. The MLF model showed higher thermal pressure value and weaker magnetic field strength in the downstream than those in the CIP model. The difference in the jump condition across the shock is also reflected in the difference in the length of the magnetotail in the two models. The magnetotail is shorter in the CIP model than that in the MLF model. We conclude that further comparative studies with finite-volume methods are necessary to verify the solution of the bow shock formation and the location of the last closed field line under northward IMF conditions.
Adapt or not: A comparison of rural migrant adaptation in two cities in China

Leading with the principle of ‘people-oriented urbanization,’ the adaptation of rural migrants in urban China has attracted increasing concerns from policy-makers and scholars. Today, China has proceeded to a new stage of urbanization. Many rural migrants prefer moving to cities near their home villages rather than to large cities, reflecting the changes in migration patterns and expectations of rural migrants. Although migrant adaptation has been repeatedly investigated in academia, researchers tend to address the topic in one host setting, while migrant adaptation in diverse urban settings has rarely been compared. This paper seeks to fill this research gap via a survey conducted in two cities with different urban settings in Jiangsu. The rural migrant adaptation experiences in the two cities are systematically compared. Our statistical results show that economic structure and living costs, on the one hand, and local regulations and socio-cultural environments, on the other hand, determine rural migrant adaptation experiences in different urban settings. Despite abundant employment opportunities in more-developed cities, the high living costs, working pressure, and strict institutional schemes significantly hamper rural migrant adaptation. In less-developed cities, limited employment opportunities and conservative socio-cultural environments hinder rural migrants from adapting in host societies. Our findings suggest that the governments of different cities need to tailor strategies to assist rural migrants in adapting in urban communities.
Establishment and application of Agrobacterium-delivered CRISPR/Cas9 system for wild tobacco (Nicotiana alata) genome editing

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR-Cas9) system has been widely applied in cultivated crops, but limited in their wild relatives. Nicotiana alata is a typical wild species of genus Nicotiana that is globally distributed as a horticultural plant and well-studied as a self-incompatibility model. It also has valuable genes for disease resistance and ornamental traits. However, it lacks an efficient genetic transformation and genome editing system, which hampers its gene function and breeding research. In this study, we developed an optimized hypocotyl-mediated transformation method for CRISPR-Cas9 delivery. The genetic transformation efficiency was significantly improved from approximately 1% to over 80%. We also applied the CRISPR-Cas9 system to target the phytoene desaturase (NalaPDS) gene in N. alata and obtained edited plants with PDS mutations with over 50% editing efficiency. To generate self-compatible N. alata lines, a polycistronic tRNA-gRNA (PTG) strategy was used to target exonic regions of allelic S-RNase genes and generate targeted knockouts simultaneously. We demonstrated that our system is feasible, stable, and high-efficiency for N. alata genome editing. Our study provides a powerful tool for basic research and genetic improvement of N. alata and an example for other wild tobacco species.
Prediction of protein interdomain linker regions by a hidden Markov model

MOTIVATION Our aim was to predict protein interdomain linker regions using sequence alone, without requiring known homology. Identifying linker regions will delineate domain boundaries, and can be used to computationally dissect proteins into domains prior to clustering them into families. We developed a hidden Markov model of linker/non-linker sequence regions using a linker index derived from amino acid propensity. We employed an efficient Bayesian estimation of the model using Markov Chain Monte Carlo, Gibbs sampling in particular, to simulate parameters from the posteriors. Our model recognizes sequence data to be continuous rather than categorical, and generates a probabilistic output. RESULTS We applied our method to a dataset of protein sequences in which domains and interdomain linkers had been delineated using the Pfam-A database. The prediction results are superior to a simpler method that also uses linker index.
Adriamycm-induced Delayed Erythropoietic Injury Expressed following Anemia Stress1

The present studies were undertaken to compare anemia-induced erythropoietic responses in femoral marrows and spleens of mice pretreated with Adriamycin (ADR) or 1-/8-D-arabinofuranosylcytosine with those of untreated age-matched controls. Mice were bled 45 or 120 days after drug treatment. The erythropoietic response to bleeding was quantitated by morphological, gravimetric, and radioiron methods 48 hr after bleeding. At 120 days after ADR, prebleeding base-line cellularity parameters were, in general, similar to those found in untreated age-matched controls. The response to the anemia stress was compared in drug-treated animals and in age-matched untreated controls, and the response deficit was expressed as residual injury (Rl). At 120 days, ADR-induced Rl was observed to be dose dependent in both femoral marrow and spleen. ADR-induced Rl in femoral marrow and spleen were similar at 45 and 120 days, with no significant recovery. Although marrow Rl was noted 45 days after 200 mg 1-/J-D-arabinofuranosylcytosine per kg, there was no Rl at 120 days. The results indicate that ADR can induce a long-lasting hematopoietic injury which is not obvious from measures of homeostatic cellularity, but which can be expressed after induction of an acute proliferative demand.
Priority-setting for hospital funding of high-cost innovative drugs and therapeutics: A qualitative institutional case study

Objectives Rising costs of innovative drugs and therapeutics (D&Ts) have led to resource allocation challenges for healthcare institutions. There is limited evidence to guide priority-setting for institutional funding of high-cost D&Ts. This study sought to identify and elaborate on the substantive principles and procedures that should inform institutional funding decisions for high-cost off-formulary D&Ts through a case study of a quaternary care paediatric hospital. Methods Semi-structured, qualitative interviews, both virtual and in-person, were conducted with institutional stakeholders (i.e. staff clinicians, senior leadership, and pharmacists) (n = 23) and two focus groups at The Hospital for Sick Children in Toronto, Canada. Participants involved in, and impacted by, high-cost off-formulary drug funding decisions were recruited through stratified, purposive sampling. Participants were approached for study involvement between July 27, 2020 and June 7, 2022. Data was analysed through reflexive thematic analysis. Results Institutional resource allocation for high-cost D&Ts was identified as ethically challenging but critical to sustainable access to novel therapies. Important substantive principles included: 1) clinical evidence of safety and efficacy, 2) economic considerations (direct costs, opportunity costs, value for money), 3) ethical principles (social justice, professional/organizational responsibility), and 4) disease-specific considerations. Multidisciplinary deliberation was identified as an essential procedural component of decision-making. Participants identified tension between innovation and the need for evidence-based decision-making; clinician and institutional responsibilities; and value for money and social justice. Participants emphasized the role of health system-level funding allocation in alleviating the financial and moral burden of decision-making by institutions. Conclusions This study identifies values and processes to aid in the development and implementation of institutional resource allocation frameworks for high-cost innovative D&Ts.
Association between ambient air pollutants and short-term mortality risks during 2015–2019 in Guangzhou, China

With the development of technology and industry, the problem of global air pollution has become difficult to ignore. We investigated the association between air pollutant concentrations and daily all-cause mortality and stratified the analysis by sex, age, and season. Data for six air pollutants [fine particulate matter (PM2.5), inhalable particles (PM10), nitric dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO)] and daily mortality rates were collected from 2015 to 2019 in Guangzhou, China. A time-series study using a quasi-Poisson generalized additive model was used to examine the relationships between environmental pollutant concentrations and mortality. Mortality data for 296,939 individuals were included in the analysis. The results showed that an increase of 10 μg/m3 in the concentrations of PM2.5, PM10, SO2, O3, NO2, and CO corresponded to 0.84% [95% confidence interval (CI): 0.47, 1.21%], 0.70% (0.44, 0.96%), 3.59% (1.77, 5.43%), 0.21% (0.05, 0.36%), 1.06% (0.70, 1.41%), and 0.05% (0.02, 0.09%), respectively. The effects of the six air pollutants were more significant for male individuals than female individuals, the cool season than the warm season, and people 75 years or older than those younger than 75 years. PM2.5, PM10, SO2, and NO2 were all associated with neoplasms and circulatory and respiratory diseases. The two-pollutant models found that PM2.5, PM10, and NO2 may independently affect the risk of mortality. The results showed that exposure to PM2.5, PM10 and NO2 may increase the risk of daily all-cause excessive mortality in Guangzhou.
Impact of Optimism on Cognitive Performance of People Living in Rural Area: Findings From a 20-Year Study in US Adults

Objectives: Mid- or early-late-life cognitive function is an indicator for developing late-life dementia. However, it is still unclear whether rural/urban living contexts provide cognitive benefits across adulthood. Further, higher optimism serves as a general protective factor for many health outcomes. The present study examines associations between rurality/urbanicity, optimism, and change in mid/late-life cognitive functions over time. Methods: Data were from waves 1 to 3 (1995–2015) of the Midlife in the United States (MIDUS) study (N = 2,507). Structural equation models examine whether long-term rural living across both waves (1–2) or intermittent rural living at one wave is associated with better cognitive function over 20 years, compared to no rural living, while controlling for prior cognitive function and covariates (baseline socio-demographics, health, and functional status). Additionally, we assessed if optimism mediates the above associations. Results: After controlling for covariates, long-term rural living (waves 1–2) was indirectly (through less optimism) associated with significantly lower levels of cognitive executive function and episodic memory in wave 3. Conclusions: While long-term rural living and cognitive outcomes have no direct association for MIDUS middle-aged and older adults, mediating roles of optimism in these associations were evident. Future investigations could examine mechanisms that underlie these risk/protective factors on late-life cognition.