Miracle-dz/UniFAR-FTUs huggingface dataset:
Computational Design of gRNAs Targeting Genetic Variants Across HIV-1 Subtypes for CRISPR-Mediated Antiviral Therapy

Clustered regularly interspaced short palindromic repeats (CRISPR)-based HIV-1 genome editing has shown promising outcomes in in vitro and in vivo viral infection models. However, existing HIV-1 sequence variants have been shown to reduce CRISPR-mediated efficiency and induce viral escape. Two metrics, global patient coverage and global subtype coverage, were used to identify guide RNA (gRNA) sequences that account for this viral diversity from the perspectives of cross-patient and cross-subtype gRNA design, respectively. Computational evaluation using these parameters and over 3.6 million possible 20-bp sequences resulted in nine lead gRNAs, two of which were previously published. This analysis revealed the benefit and necessity of considering all sequence variants for gRNA design. Of the other seven identified novel gRNAs, two were of note as they targeted interesting functional regions. One was a gRNA predicted to induce structural disruption in the nucleocapsid binding site (Ψ), which holds the potential to stop HIV-1 replication during the viral genome packaging process. The other was a reverse transcriptase (RT)-targeting gRNA that was predicted to cleave the subdomain responsible for dNTP incorporation. CRISPR-mediated sequence edits were predicted to occur on critical residues where HIV-1 has been shown to develop resistance against antiretroviral therapy (ART), which may provide additional evolutionary pressure at the DNA level. Given these observations, consideration of broad-spectrum gRNAs and cross-subtype diversity for gRNA design is not only required for the development of generalizable CRISPR-based HIV-1 therapy, but also helps identify optimal target sites.
A Golgi-Localized Sodium/Hydrogen Exchanger Positively Regulates Salt Tolerance by Maintaining Higher K+/Na+ Ratio in Soybean

Salt stress caused by soil salinization, is one of the main factors that reduce soybean yield and quality. A large number of genes have been found to be involved in the regulation of salt tolerance. In this study, we characterized a soybean sodium/hydrogen exchanger gene GmNHX5 and revealed its functional mechanism involved in the salt tolerance process in soybean. GmNHX5 responded to salt stress at the transcription level in the salt stress-tolerant soybean plants, but not significantly changed in the salt-sensitive ones. GmNHX5 was located in the Golgi apparatus, and distributed in new leaves and vascular, and was induced by salt treatment. Overexpression of GmNHX5 improved the salt tolerance of hairy roots induced by soybean cotyledons, while the opposite was observed when GmNHX5 was knockout by CRISPR/Cas9. Soybean seedlings overexpressing GmNHX5 also showed an increased expression of GmSOS1, GmSKOR, and GmHKT1, higher K+/Na+ ratio, and higher viability when exposed to salt stress. Our findings provide an effective candidate gene for the cultivation of salt-tolerant germplasm resources and new clues for further understanding of the salt-tolerance mechanism in plants.
A Potential Mechanism Underlying the Therapeutic Effects of Progesterone and Allopregnanolone on Ketamine-Induced Cognitive Deficits

Ketamine exposure can model cognitive deficits associated with schizophrenia. Progesterone (PROG) and its active metabolite allopregnanolone (ALLO) have neuroprotective effects and the pathway involving progesterone receptor membrane component 1 (PGRMC1), epidermal growth factor receptor (EGFR), glucagon-like peptide-1 receptor (GLP-1R), phosphatidylinositol 3 kinase (PI3K), and protein kinase B (Akt) appears to play a key role in their neuroprotection. The present study aimed to investigate the effects of PROG (8,16 mg kg−1) and ALLO (8,16 mg kg−1) on the reversal of cognitive deficits induced by ketamine (30 mg kg−1) via the PGRMC1 pathway in rat brains, including hippocampus and prefrontal cortex (PFC). Cognitive performance was evaluated by Morris water maze (MWM) test. Western blot and real-time quantitative polymerase chain reaction were utilized to assess the expression changes of protein and mRNA. Additionally, concentrations of PROG and ALLO in plasma, hippocampus and PFC were measured by a liquid chromatography-tandem mass spectrometry method. We demonstrated that PROG or ALLO could reverse the impaired spatial learning and memory abilities induced by ketamine, accompanied with the upregulation of PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway. Additionally, the coadministration of AG205 abolished their neuroprotective effects and induced cognitive deficits similar with ketamine. More importantly, PROG concentrations were markedly elevated in PROG-treated groups in hippocampus, PFC and plasma, so as for ALLO concentrations in ALLO-treated groups. Interestingly, ALLO (16 mg kg−1) significantly increased the levels of PROG. These findings suggest that PROG can exert its neuroprotective effects via activating the PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway in the brain, whereas ALLO also restores cognitive deficits partially via increasing the level of PROG in the brain to activate the PGRMC1 pathway.
Prognostic Value of an Autophagy-Related Five-Gene Signature for Lower-Grade Glioma Patients

Background: Molecular characteristics can be good indicators of tumor prognosis and have been introduced into the classification of gliomas. The prognosis of patients with newly classified lower-grade gliomas (LGGs, including grade 2 and grade 3 gliomas) is highly heterogeneous, and new molecular markers are urgently needed. Methods: Autophagy related genes (ATGs) were obtained from Human Autophagy Database (HADb). From the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), gene expression profiles including ATG expression information and patient clinical data were downloaded. Cox regression analysis, receiver operating characteristic (ROC) analysis, Kaplan–Meier analysis, random survival forest algorithm (RSFVH) and stratification analysis were performed. Results: Through univariate Cox regression analysis, we found a total of 127 ATGs associated with the prognosis of LGG patients from TCGA dataset and a total of 131 survival-related ATGs from CGGA dataset. Using TCGA dataset as the training group (n = 524), we constructed a five-ATG signature (including BAG1, BID, MAP1LC3C, NRG3, PTK6), which could divide LGG patients into two risk groups with significantly different overall survival (Log Rank P < 0.001). Then we confirmed in the independent CGGA dataset that the five-ATG signature had the ability to predict prognosis (n = 431, Log Rank P < 0.001). We further discovered that the predictive ability of the five-ATG signature was better than the existing clinical indicators and IDH mutation status. In addition, the five-ATG signature could further classify patients after receiving radiotherapy or chemotherapy into groups with different prognosis. Conclusions: We identified a five-ATG signature that could be a reliable prognostic marker and might be therapeutic targets for autophagy therapy for LGG patients.
Immune Trait Shifts in Association With Tobacco Smoking: A Study in Healthy Women

Tobacco smoking is known to impact circulating levels of major immune cells populations, but its effect on specific immune cell subsets remains poorly understood. Here, using high-resolution data from 223 healthy women (25 current and 198 never smokers), we investigated the association between smoking status and 35,651 immune traits capturing immune cell subset frequencies. Our results confirmed that active tobacco smoking is associated with increased frequencies of circulating CD8+ T cells expressing the CD25 activation marker. Moreover, we identified novel associations between smoking status and relative abundances of CD8+ CD25+ memory T cells, CD8+ memory T cells expressing the CCR4 chemokine receptor, and CD4+CD8+ (double-positive) CD25+ T cells. We also observed, in current smokers, a decrease in the relative frequencies of CD4+ T cells expressing the CD38 activation marker and an increase in class-switched memory B cell isotypes IgA, IgG, and IgE. Finally, using data from 135 former female smokers, we showed that the relative frequencies of immune traits associated with active smoking are usually completely restored after smoking cessation, with the exception of subsets of CD8+ and CD8+ memory T cells, which persist partially altered. Our results are consistent with previous findings and provide further evidence on how tobacco smoking shapes leukocyte cell subsets proportion toward chronic inflammation.
Role of weak hydrogen bonds in the crystal structures of phenazine, 5,10-dihydrophenazine and their 1:1 and 3:1 molecular complexes

Phenazine (1) and 5,10-dihydrophenazine (2) form not only a 1:1 complex (3), as expected from N–H···N hydrogen bond requirements, but surprisingly also a 3:1 complex (4). Single crystal X-ray analyses of compound 2 and complexes 3 and 4 have been carried out. While the overall packing in complex 3 is as efficient as in pure 1 and 2, acidic C–H groups, which contribute actively to the structural assembly in pure 2, are not involved in hydrogen bonding in 3. It is shown that the quest for hydrogen bonding by these C–H groups steers the formation of complex 4 with an unprecedented N–H···N and C–H···N hydrogen bond mediated tape structure.
A Survey of k Nearest Neighbor Algorithms for Solving the Class Imbalanced Problem

k nearest neighbor (kNN) is a simple and widely used classifier; it can achieve comparable performance with more complex classifiers including decision tree and artificial neural network. Therefore, kNN has been listed as one of the top 10 algorithms in machine learning and data mining. On the other hand, in many classification problems, such as medical diagnosis and intrusion detection, the collected training sets are usually class imbalanced. In class imbalanced data, although positive examples are heavily outnumbered by negative ones, positive examples usually carry more meaningful information and are more important than negative examples. Similar to other classical classifiers, kNN is also proposed under the assumption that the training set has approximately balanced class distribution, leading to its unsatisfactory performance on imbalanced data. In addition, under a class imbalanced scenario, the global resampling strategies that are suitable to decision tree and artificial neural network often do not work well for kNN, which is a local information-oriented classifier. To solve this problem, researchers have conducted many works for kNN over the past decade. This paper presents a comprehensive survey of these works according to their different perspectives and analyzes and compares their characteristics. At last, several future directions are pointed out.
Comment on “On the original proof by reductio ad absurdum of the Hohenberg–Kohn theorem for many-electron Coulomb systems”

We argue with Kryachko's criticism [Int J Quantum Chem 2005, 103, 818] of the original proof of the second Hohenberg-Kohn theorem. The Kato cusp condition can be used to refute a to-be-refuted statement as an alternative to the original proof by Hohenberg and Kohn applicable for Coulombic systems. Since alternative ways to prove falseness of the to-be-refuted statement in a reduction ad absurdum proof do not exclude each other, Kryachko's criticism is not justified.
Controller and Triggering Mechanism Co-design for Control Over Time-Slotted Networks

This article considers the control of linear time-invariant systems over a time-slotted communication network, which supports infrequent deterministic transmission slots and additional opportunistic transmission slots that can only be used if the network traffic satisfies a desired traffic specification. For two scenarios, controllers as well as combined time-based and event-based triggering mechanisms are designed such that three goals can be jointly achieved. The first goal is to guarantee asymptotic stability by using the deterministic slots, independent of any knowledge about the use of opportunistic transmissions. Second, the triggering mechanisms are designed such that the opportunistic transmissions satisfy a given token bucket traffic specification. As a third goal, the opportunistic transmission decisions should be dependent on the possible performance improvement attributed to the transmitted message. This property is formalized in the newly defined concept of performance-oriented triggering. The two derived controllers and triggering mechanisms are demonstrated using a numerical example.
Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies

Objective We performed a meta-analysis of observational studies to quantify the magnitude of the association between non-alcoholic fatty liver disease (NAFLD) and risk of extrahepatic cancers. Design We systematically searched PubMed, Scopus and Web of Science databases from the inception date to 30 December 2020 using predefined keywords to identify observational cohort studies conducted in individuals, in which NAFLD was diagnosed by imaging techniques or International Classification of Diseases codes. No studies with biopsy-proven NAFLD were available for the analysis. Meta-analysis was performed using random-effects modelling. Results We included 10 cohort studies with 182 202 middle-aged individuals (24.8% with NAFLD) and 8485 incident cases of extrahepatic cancers at different sites over a median follow-up of 5.8 years. NAFLD was significantly associated with a nearly 1.5-fold to twofold increased risk of developing GI cancers (oesophagus, stomach, pancreas or colorectal cancers). Furthermore, NAFLD was associated with an approximately 1.2-fold to 1.5-fold increased risk of developing lung, breast, gynaecological or urinary system cancers. All risks were independent of age, sex, smoking, obesity, diabetes or other potential confounders. The overall heterogeneity for most of the primary pooled analyses was relatively low. Sensitivity analyses did not alter these findings. Funnel plots did not reveal any significant publication bias. Conclusion This large meta-analysis suggests that NAFLD is associated with a moderately increased long-term risk of developing extrahepatic cancers over a median of nearly 6 years (especially GI cancers, breast cancer and gynaecological cancers). Further research is required to decipher the complex link between NAFLD and cancer development.
Development of the integrated New Jersey Safety and Health Outcomes (NJ-SHO) data warehouse: catalysing advancements in injury prevention research

Objective Our objective was to describe the development of the New Jersey Safety and Health Outcomes (NJ-SHO) data warehouse—a unique and comprehensive data source that integrates state-wide administrative databases in NJ to enable the field of injury prevention to address critical, high-priority research questions. Methods We undertook an iterative process to link data from six state-wide administrative databases from NJ for the period of 2004 through 2018: (1) driver licensing histories, (2) traffic-related citations and suspensions, (3) police-reported crashes, (4) birth certificates, (5) death certificates and (6) hospital discharges (emergency department, inpatient and outpatient). We also linked to electronic health records of all NJ patients of the Children’s Hospital of Philadelphia network, census tract-level indicators (using geocoded residential addresses) and state-wide Medicaid/Medicare data. We used several metrics to evaluate the quality of the linkage process. Results After the linkage process was complete, the NJ-SHO data warehouse included linked records for 22.3 million distinct individuals. Our evaluation of this linkage suggests that the linkage was of high quality: (1) the median match probability—or likelihood of a match being true—among all accepted pairs was 0.9999 (IQR: 0.9999–1.0000); and (2) the false match rate—or proportion of accepted pairs that were false matches—was 0.0063. Conclusions The resulting NJ-SHO warehouse is one of the most comprehensive and rich longitudinal sources of injury data to date. The warehouse has already been used to support numerous studies and is primed to support a host of rigorous studies in the field of injury prevention.
Variation, development and pragmatic uses of innit in the language of British adults and teenagers1

The so-called invariant tags, such as eh, okay, right and yeah, are extremely frequent in general English speech and have been studied extensively in recent years, especially in the spoken expression of teenagers, where they are a very common feature. In this article I focus on innit, as in She love her chocolate innit? and It was good innit? For this purpose, I analyse and discuss data extracted from two comparable corpora of teen speech: the Bergen Corpus of London Teenage Language (COLT), compiled in 1993, and the Linguistic Innovators Corpus (LI), created in 2004. The analysis considers the syntactic, semantic and pragmatic features of the expression, and asks three fundamental questions: has innit remained stable in use over time or has it increased in frequency? Has innit preserved its original grammatical features, or has it undergone notable changes? To what extent is innit especially associated with teentalk, at least in London speech, rather than with the speech of adults? Contrasts are also drawn with the standard tag isn't it. Findings confirm that innit is typical of the language of London teenagers and has not gone out of use; on the contrary, its frequency has increased over the last few years. In contrast, the proportion of tokens found in the language of their adult counterparts is rather marginal. At present, innit conserves syntactic features of its own: it does not follow the regular question tag formation rules and can represent not only the verb be but also do, have and most of the modal verbs. Furthermore, it continues to show a high degree of flexibility in the sentence, occurring not only in final but also in initial and medial positions. Finally, it appears that innit should no longer be regarded as a simple invariant tag. It tends to behave more and more like a pragmatic marker serving to express the speaker's attitude to the content of the message, thus often reflecting the relationship between the participants in the interaction, and also contributing to the organisation of the discourse. In this respect, two new discourse functions of innit are identified and described: emphatic and text organiser.
Photoinitiated cationic polymerization of epoxides

Difunctional epoxy monomers have been polymerized cationically by UV irradiation in the presence of a triarylsulfonium photoinitiator. The curing process was followed quantitatively by monitoring the disappearance of the epoxy group by infrared spectroscopy and the insolubilization and hardening of the resin upon UV exposure. The addition of epoxidized soyabean oil (ESO) to an aromatic diepoxide was shown to accelerate the crosslinking reaction with formation of a tight polymer network. The photoinitiated copolymerization of ESO with a cycloaliphatic diepoxide proceeds extensively and leads within seconds to a fully cured insoluble material showing increased hardness, flexibility and scratch resistance. Interpenetrating polymer networks have been generated by a short UV-irradiation of blends of acrylate and epoxy monomers. © 2001 Society of Chemical Industry
Arti�cial intelligence for reduced dose 18F-FDG PET examinations: A real-world deployment through a standardized framework and business case assessment

Background To determine whether arti�cial intelligence (AI) processed PET/CT images of reduced by 33% administered 18-F FDG activity acquired in a single center, were non-inferior to native scans and if so to assess the potential impact of commercialization. Methods SubtlePET™ AI was introduced in a PET/CT center in Italy. Eligible patients referred for 18F-FDG PET/CT were prospectively enrolled. Administered 18F-FDG was reduced to two-thirds of standard dose. Patients underwent one low-dose CT and two sequential PET scans; ‘PET-processed’ with reduced dose and standard acquisition time, and ‘PET-native’ with an elapsed time to simulate standard acquisition time and dose. PET-processed images were reconstructed using SubtlePET™. PET-native images were de�ned as the standard of reference. The datasets were anonymized and independently evaluated in random order by four blinded readers. The evaluation included subjective image quality (IQ) assessment, lesion detectability and assessment of business bene�ts. Results From February to April 2020, 61 patients were prospectively enrolled. Subjective IQ was not signi�cantly different between datasets (4.62±0.23, p=0.237) for all scanner models, with ‘almost perfect’ inter-reader agreement. There was no signi�cant difference between datasets in lesions’ detectability, target lesion mean SUVmax value and liver mean SUVmean value (182.75/181.75 [SD:0.71], 9.8/11.4 [SD:1.13], 2.1/1.9 [SD:0.14] respectively). No false-positive lesions were reported in PET-processed examinations. Agreed SubtlePET™ price per examination was 15-20% of FDG savings. Conclusion This is the �rst real-world study to demonstrate the non-inferiority of AI processed 18F-FDG PET/CT examinations obtained with 66% standard dose and a methodology to de�ne the AI solution price.
Oxidation Reactions of Lanthanide Cations with N2O and O2: Periodicities in Reactivity

The oxidation reactions of all of the lanthanide cations (except Pm+) with N2O and O2 have been investigated using the inductively coupled plasma selected-ion flow tube (ICP/SIFT) technique. Lanthanide cations were generated in an inductively coupled plasma (ICP) ion source. Observations are reported for the reactions of La+, Ce+, Pr+, Nd+, Sm+, Eu+, Gd+, Tb+, Dy+, Ho+, Er+, Tm+, Yb+, and Lu+ with N2O and O2 at room temperature (295 ± 2 K) in helium at a total pressure of 0.35 ± 0.02 Torr. Measured reaction rates varied from close to the predicted ion−molecule collision rate down to less than 0.1% efficiency. Observations are rationalized in terms of reaction thermodynamics and electronic structure effects. The efficiency for the reactions with N2O was found to decrease as the energy required to promote the metal-ion electron from the 4fn5d06s1 to the 4fn-15d16s1 configuration increases. Remarkable and different Arrhenius-like correlations are found in the N2O reactivity of the early and late lanthanide c.
Kinetics of glycolysis of poly(ethylene terephthalate) melts

The reaction of poly(ethylene terephthalate) (PET) melts with ethylene glycol was examined in a pressure reactor at temperatures above 245°C. The reaction rate was found to depend on temperature and on the concentrations of liquid ethylene glycol and of ethylene diester groups in the polymer. A kinetic model proposed for the initial period of the reaction was found to be consistent with experimental data. It was found that internal catalysis by ethylene glycol does not play an important role in the glycolytic depolymerization of PET. The rate constants for glycolysis were calculated for three different temperatures, yielding an activation energy of 92 kJ/mol. Zinc salts, which have a catalytic effect on glycolysis of PET below 245°C, do not appear to influence glycolysis rates above that temperature. © 1994 John Wiley & Sons, Inc.