Miracle-dz/UniFAR-FTUs huggingface dataset:
CRISPRing future medicines

ABSTRACT Introduction: The ability to engineer mammalian genomes in a quick and cost-effective way has led to rapid adaptation of CRISPR technology in biomedical research. CRISPR-based engineering has the potential to accelerate drug discovery, to support the reduction of high attrition rate in drug development and to enhance development of cell and gene-based therapies. Areas covered: How CRISPR technology is transforming drug discovery is discussed in this review. From target identification to target validation in both in vitro and in vivo models, CRISPR technology is positively impacting the early stages of drug development by providing a straightforward way to genome engineering. This property also attracted attention for CRISPR application in the cell and gene therapy area. Expert opinion: CRISPR technology is rapidly becoming the preferred tool for genome engineering and nowadays it is hard to imagine the drug discovery pipeline without this technology. With the years to come, CRISPR technology will undoubtedly be further refined and will flourish into a mature technology that will play a key role in supporting genome engineering requirements in the drug discovery pipeline as well as in cell and gene therapy development.
Understanding Contraceptive Needs of Women Who Inject Drugs in Orange County: A Qualitative Study

Objectives: Women with opioid use disorder experience higher rates of unintended pregnancy compared with the general US population. Our aim was to examine the factors that may affect access to desired contraception for women who use injection drugs. Methods: Using purposive sampling, we conducted semi-structured interviews pertaining to contraceptive use with 14 women ages 18 to 44 who were current users of injection drugs living in Orange County, CA between March and December 2019. Interviews were transcribed, coded, and analyzed using grounded theory. Results: Participants discussed logistical barriers, including homelessness and lack of transportation, as well as perceived barriers, such as a belief in the inability to become pregnant while using drugs, that affect access to contraceptive care. Women also discussed the factors that motivate them to use contraception despite these barriers, including the desire for sobriety before becoming pregnant and fear of harming a fetus while using substances. Some participants expressed feeling uncomfortable disclosing substance use to their healthcare providers out of concern for stigmatization. Several points of access for contraceptive care were elucidated, including visits for primary and postpartum care, as well as in carceral spaces. Finally, participants expressed a desire to obtain contraceptive services at a local syringe exchange program due to trusting relationships with providers and increased ease of access. Conclusions: Our findings highlight several causative factors for the unmet contraceptive need among women who use injection drugs, and suggest that syringe exchange programs represent a unique access point for the provision of contraceptive care for this population.
Analysis of Pedestrian Street-Crossing Decision-Making Based on Vehicle Deceleration-Safety Gap

Numerous traffic crashes occur every year on zebra crossings in China. Pedestrians are vulnerable road users who are usually injured severely or fatally during human-vehicle collisions. The development of an effective pedestrian street-crossing decision-making model is essential to improving pedestrian street-crossing safety. For this purpose, this paper carried out a naturalistic field experiment to collect a large number of vehicle and pedestrian motion data. Through interviewed with many pedestrians, it is found that they pay more attention to whether the driver can safely brake the vehicle before reaching the zebra crossing. Therefore, this work established a novel decision-making model based on the vehicle deceleration-safety gap (VD-SGM). The deceleration threshold of VD-SGM was determined based on signal detection theory (SDT). To verify the performance of VD-SGM proposed in this work, the model was compared with the Raff model. The results show that the VD-SGM performs better and the false alarm rate is lower. The VD-SGM proposed in this work is of great significance to improve pedestrians’ safety. Meanwhile, the model can also increase the efficiency of autonomous vehicles.
Long-Term Surgical Results of Skip Pedicle Screw Fixation for Patients with Adolescent Idiopathic Scoliosis: A Minimum-Ten-Year Follow-Up Study

Skip pedicle screw fixation for adolescent idiopathic scoliosis (AIS) requires fewer screws and can reduce the risk of neurovascular injury as compared with segmental pedicle screw fixation. However, the long-term impact of screw number reduction on correction and clinical results is unclear. This study examined the 10-year post-operative outcomes of skip pedicle screw fixation for patients with AIS. We reviewed the outcomes of 30 patients who underwent skip pedicle screw fixation for AIS. Radiological and clinical findings were assessed before and immediately, 2 years, and 10 years after surgery in the remaining 25 patients. The mean Cobb angle of the main curve preoperatively and immediately, 2 years, and 10 years post-operatively was 59.4°, 23.4°, 25.8°, and 25.60°, respectively, and was significantly improved at all post-surgical time points (all p < 0.001). The mean correction rate immediately after surgery was 60.8%, and the correction loss rate at the observation end point was 4.8%. The Cobb angle of the lumbar curve was significantly improved immediately after surgery, and the correction persisted until 10 years post-operatively. Remarkable gains were observed for most Scoliosis Research Society-22 patient questionnaire sub-scores at the final follow-up versus preoperative assessments. In conclusion, good correction of the AIS deformity by skip pedicle screw fixation was well maintained over a long follow-up period of 10 years, with clinically meaningful gains in Society-22 patient questionnaire sub-scores.
β-Glucan Metabolic and Immunomodulatory Properties and Potential for Clinical Application

β-glucans are complex polysaccharides that are found in several plants and foods, including mushrooms. β-glucans display an array of potentially therapeutic properties. β-glucans have metabolic and gastro-intestinal effects, modulating the gut microbiome, altering lipid and glucose metabolism, reducing cholesterol, leading to their investigation as potential therapies for metabolic syndrome, obesity and diet regulation, gastrointestinal conditions such as irritable bowel, and to reduce cardiovascular and diabetes risk. β-glucans also have immune-modulating effects, leading to their investigation as adjuvant agents for cancers (solid and haematological malignancies), for immune-mediated conditions (e.g., allergic rhinitis, respiratory infections), and to enhance wound healing. The therapeutic potential of β-glucans is evidenced by the fact that two glucan isolates were licensed as drugs in Japan as immune-adjuvant therapy for cancer in 1980. Significant challenges exist to further clinical testing and translation of β-glucans. The diverse range of conditions for which β-glucans are in clinical testing underlines the incomplete understanding of the diverse mechanisms of action of β-glucans, a key knowledge gap. Furthermore, important differences appear to exist in the effects of apparently similar β-glucan preparations, which may be due to differences in sources and extraction procedures, another poorly understood issue. This review will describe the biology, potential mechanisms of action and key therapeutic targets being investigated in clinical trials of β-glucans and identify and discuss the key challenges to successful translation of this intriguing potential therapeutic.
Association between arterial stiffness and the clustering of metabolic syndrome risk factors: a systematic review and meta-analysis

Supplemental Digital Content is available in the text Objectives: Metabolic syndrome (MetS) is a cluster of different cardiometabolic risk factors (CMRFs), and its different combinations with other CMRFs, such as arterial stiffness have been hypothesized to explain, at least partially, increased risk of cardiovascular disease. Thus, in this systematic review and meta-analysis, we aimed to synthesize the evidence regarding the association between the clustering of MetS-related CMRFs and arterial stiffness measured using pulse wave velocity (PWV). Methods: Original studies analysing the association between arterial stiffness, measured using PWV, and MetS were systematically searched. Pooled effect size estimates and their respective 95% confidence intervals (CI) were calculated using the DerSimonian and Laird method for two separate analyses: the diagnosis of MetS and PWV values and the number of CMRFs and PWV values. Results: Moderate effect size estimates were observed between MetS and PWV (0.68, 95% CI: 0.54–0.82) with a slightly higher effect size for the low-risk compared with the high-risk population group (0.75, 95% CI: 0.58–0.92; and 0.51, 95% CI: 0.32–0.82, respectively). A trend between the number of MetS-related CMRFs and PWV was found with the pooled effect size nearly doubling as the number of MetS-related CMRFs increased, 0.11 (95% CI: 0.04–0.17) for one MetS-related CMRF, 0.26 (95% CI: 0.13–0.4) for two, and 0.4 (95% CI: 0.2–0.6) for three or more. Conclusion: These results demonstrated a clinically relevant association between MetS and PWV and an increasing trend in PWV values, such as a MetS-related CMRF increase. Although these results should be considered cautiously because of the considerable heterogeneity, our findings reinforce the rationale of MetS as an aggregation of risk factors with common causes, which could provide additional useful information to guide clinical management.
Highly Efficient Antimicrobial and Antifouling Surface Coatings with Triclosan-Loaded Nanogels

Multifunctional nanogel coatings provide a promising antimicrobial strategy against biomedical implant-associated infections. Nanogels can create a hydrated surface layer to promote antifouling properties effectively. Further modification of nanogels with quaternary ammonium compounds (QACs) potentiates antimicrobial activity owing to their positive charges along with the presence of a membrane-intercalating alkyl chain. This study effectively demonstrates that poly(N-isopropylacrylamide-co-N-[3(dimethylamino)propyl]methacrylamide) (P(NIPAM-co-DMAPMA)-based nanogel coatings possess antifouling behavior against S. aureus ATCC 12600, a Gram-positive bacterium. Through the tertiary amine in the DMAPMA comonomer, nanogels are quaternized with a 1-bromo-dodecane chain via an N-alkylation reaction. The alkylation introduces the antibacterial activity due to the bacterial membrane binding and the intercalating ability of the aliphatic QAC. Subsequently, the quaternized nanogels enable the formation of intraparticle hydrophobic domains because of intraparticle hydrophobic interactions of the aliphatic chains allowing for Triclosan incorporation. The coating with Triclosan-loaded nanogels shows a killing efficacy of up to 99.99% of adhering bacteria on the surface compared to nonquaternized nanogel coatings while still possessing an antifouling activity. This powerful multifunctional coating for combating biomaterial-associated infection is envisioned to greatly impact the design approaches for future clinically applied coatings.
The relationship between hippocampal subfield volumes and autobiographical memory persistence

Structural integrity of the human hippocampus is widely acknowledged to be necessary for the successful encoding and retrieval of autobiographical memories. However, evidence for an association between hippocampal volume and the ability to recall such memories in healthy individuals is mixed. Here we examined this issue further by combining two approaches. First, we focused on the anatomically distinct subregions of the hippocampus where more nuanced associations may be expressed compared to considering the whole hippocampal volume. A manual segmentation protocol of hippocampal subregions allowed us to separately calculate the volumes of the dentate gyrus/CA4, CA3/2, CA1, subiculum, pre/parasubiculum and uncus. Second, a critical feature of autobiographical memories is that they can span long time periods, and so we sought to consider how memory details persist over time by conducting a longitudinal study whereby participants had to recall the same autobiographical memories on two visits spaced 8 months apart. Overall, we found that there was no difference in the total number of internal (episodic) details produced at Visits 1 and 2. However, further probing of detail subcategories revealed that specifically the amount of subjective thoughts and emotions included during recall had declined significantly by the second visit. We also observed a strong correlation between left pre/parasubiculum volume and the amount of autobiographical memory internal details produced over time. This positive relationship was evident for particular facets of the memories, with remembered events, perceptual observations and thoughts and emotions benefitting from greater volume of the left pre/parasubiculum. These preliminary findings expand upon existing functional neuroimaging evidence by highlighting a potential link between left pre/parasubiculum volume and autobiographical memory. A larger pre/parasubiculum appears not only to protect against memory decay, but may possibly enhance memory persistence, inviting further scrutiny of the role of this brain region in remote autobiographical memory retrieval.
CD146/sCD146 in the Pathogenesis and Monitoring of Angiogenic and Inflammatory Diseases

CD146 is a cell adhesion molecule expressed on endothelial cells, as well as on other cells such as mesenchymal stem cells and Th17 lymphocytes. This protein also exists in a soluble form, whereby it can be detected in biological fluids, including the serum or the cerebrospinal fluid (CSF). Some studies have highlighted the significance of CD146 and its soluble form in angiogenesis and inflammation, having been shown to contribute to the pathogenesis of many inflammatory autoimmune diseases, such as systemic sclerosis, mellitus diabetes, rheumatoid arthritis, inflammatory bowel diseases, and multiple sclerosis. In this review, we will focus on how CD146 and sCD146 contribute to the pathogenesis of the aforementioned autoimmune diseases and discuss the relevance of considering it as a biomarker in these pathologies.
Synthesis of New Tyrosol‐Based Phosphodiester Derivatives: Effect on Amyloid β Aggregation and Metal Chelation Ability

Alzheimer's disease (AD) is a multifactorial pathology that requires multifaceted agents able to address its peculiar nature. Increasing evidence has shown that aggregation of amyloid β (Aβ) and oxidative stress are strictly interconnected, and their modulation might have a positive and synergic effect in contrasting AD‐related impairments. Herein, a new and efficient fragment‐based approach towards tyrosol phosphodiester derivatives (TPDs) has been developed starting from suitable tyrosol building blocks and exploiting the well‐established phosphoramidite chemistry. The antioxidant activity of new TPDs has been tested as well as their ability to inhibit Aβ protein aggregation. In addition, their metal chelating ability has been evaluated as a possible strategy to develop new natural‐based entities for the prevention or therapy of AD. Interestingly, TPDs containing a catechol moiety have demonstrated highly promising activity in inhibiting the aggregation of Aβ40 and a strong ability to chelate biometals such as CuII and ZnII.
Transition of Serum Cytokine Concentration in Rickettsia japonica Infection

(1) Background. Rickettsia japonica (R. japonica) infection induces severe inflammation, and the disappearance of eosinophil in the acute stage is one of the phenomena. (2) Materials and Methods. In the current study, we measured the serum concentrations of Th1, Th2, and Th17 cytokines in the acute and recovery stages. (3) Results. In the acute phase, IL-6 and IFN-γ levels were elevated and we speculated that they played a role as a defense mechanism against R. japonica. The high concentration of IFN-γ suppressed the differentiation of eosinophil and induced apoptosis of eosinophil, leading to the disappearance of eosinophil. On day 7, IL-6 and IFN-γ concentrations were decreased, and Th2 cytokines such as IL-5 and IL-9 were slightly increased. On day 14, eosinophil count recovered to the normal level. The transition of serum cytokine concentration in R. japonica infection was presented. (4) Conclusions. IL-6 and IFN-γ seem to be critical cytokines as defense mechanism against R. japonica in the acute phase, and this may deeply connect to the decrease of eosinophil.
Bta-miR-376a Targeting KLF15 Interferes with Adipogenesis Signaling Pathway to Promote Differentiation of Qinchuan Beef Cattle Preadipocytes

Simple Summary Our study demonstrated that bta-miR-376a negatively regulates adipocyte proliferation and differentiation by targeting the adipogenesis signaling pathway and is thus a novel regulator of development in Qinchuan beef cattle. These findings contribute to a better understanding of adipogenesis regulated by miRNA and provide an important reference for studies on beef intramuscular fat. Abstract Intramuscular fat (IMF) is a quality index associated with the taste and juiciness of meat. The deposition of IMF is affected by genetic and non-genetic factors, such as age, slaughter location, gender of the animal, and diet. Micro-ribonucleic acids (miRNA) are transcriptional regulators involved in adipogenesis, but the specific role of miR-376a in regulation of bovine adipocytes remains unknown. Our findings indicated that miR-376a was a potential negative regulator of bovine adipocyte differentiation. A bta-miR-376a mimic inhibited mRNA and protein expression of the marker genes, CDK1, CDK2, PCNA, C/EBPα, FAS, and PPAR γ, and significantly reduced ratios (%) of S-phase cells, the number of cells stained with 5-ethynyl-2′-deoxyuridine, and adipocyte proliferation. Oil red O staining and triglyceride content analysis also confirmed that bta-miR-376a was involved in adipocyte differentiation. Luciferase activities confirmed that Krüppel-like transcription factor 15 (KLF15) was a direct target gene of bta-miR-376a, and that KLF15 was a key transcription factor in adipogenesis. Therefore, bta-miR-376a might be a target for increasing beef IMF.
Neuromuscular and Clinical Recovery in Thoracic Surgical Patients Reversed With Neostigmine or Sugammadex

BACKGROUND: Patients undergoing thoracoscopic procedures may be at high-risk for incomplete neuromuscular recovery and associated complications. The aim of this clinical investigation was to assess the incidence of postoperative residual neuromuscular blockade in adult thoracic surgical patients administered neostigmine or sugammadex when optimal dosing and reversal strategies for these agents were used. The effect of choice of reversal agent on hypoxemic events and signs and symptoms of muscle weakness were also determined. Additionally, operative conditions in each group were graded by surgeons performing the procedures. METHODS: Two hundred patients undergoing thoracoscopic surgical procedures were enrolled in this nonrandomized controlled trial. One hundred consecutive patients maintained at moderate levels of neuromuscular blockade were reversed with neostigmine (neostigmine group) followed by 100 consecutive patients given sugammadex to antagonize deeper levels of neuromuscular blockade (sugammadex group). Anesthetic and neuromuscular management were standardized. Surgeons rated operative conditions at the conclusion of the procedure on a 4-point scale (grade 1 = excellent to grade 4 = poor). Train-of-four ratios were measured immediately before extubation and at PACU admission (primary outcomes). Postoperatively, patients were assessed for adverse respiratory events and 11 signs and 16 symptoms of muscle weakness. RESULTS: The 2 groups were similar in intraoperative management characteristics. The percentage of patients with residual neuromuscular blockade, defined as a normalized train-of-four ratio <0.9, was significantly greater in the neostigmine group than the sugammadex group at both tracheal extubation (80% vs 6%, respectively, P < .0001) and PACU admission (61% vs 1%, respectively, P < .0001). Patients in the neostigmine group had less optimal operative conditions (median score 2 [good] versus 1 [excellent] in the sugammadex group; P < .0001), and more symptoms of muscle weakness were present in these subjects (median number [interquartile range] 4 [1–8] vs 1 [0–2] in the sugammadex group, P < .0001). No differences between groups in adverse airway events were observed. CONCLUSIONS: Despite the application of strategies documented to reduce the risk of residual neuromuscular blockade, a high percentage of thoracoscopic patients whose neuromuscular blockade was reversed with neostigmine were admitted to the PACU with clinical evidence of residual paralysis. In contrast, muscle weakness was rarely observed in patients whose neuromuscular blockade was antagonized with sugammadex.
Citrate utilization under anaerobic environment in Escherichia coli is under direct control of Fnr and indirect control of ArcA and Fnr via CitA-CitB system.

Most Escherichia coli (E. coli) strains do not cause disease, naturally living in the lower intestine and is expelled into the environment within fecal matter. E. coli can utilize citrate under anaerobic conditions but not aerobic conditions. However, the underlying regulatory mechanisms are poorly understood. In this study, we explored regulatory mechanisms of citrate fermentation genes by global regulators ArcA and Fnr under anaerobic conditions. A gel mobility shift assay showed that the regulator proteins ArcA and Fnr bind to the promoter region localized between the citAB and citCDEFXGT operons. Subsequent assays confirmed that ArcA indirectly control the expression of citrate fermentation genes via regulating CitA-CitB system, while Fnr directly regulate but also indirect modulate citrate fermentation genes via control CitA-CitB system. Deletions of arcA and fnr significantly reduced the growth of Escherichia coli in M9 medium with a citrate carbon source. We conclude that both ArcA and Fnr can indirectly control the citrate utilization via CitA-CitB system, while, Fnr can also directly regulate the expression of citrate fermentation genes in E. coli under anaerobic conditions. This article is protected by copyright. All rights reserved.