Miracle-dz/UniFAR-FTUs huggingface dataset:
Fluorine Modifications Contribute to Potent Antiviral Activity against Highly Drug-Resistant HIV-1 and Favorable Blood-Brain Barrier Penetration Property of Novel Central Nervous System-Targeting HIV-1 Protease Inhibitors In Vitro

To date, there are no specific treatment regimens for HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). Here, we report that two newly generated CNS-targeting HIV-1 protease (PR) inhibitors (PIs), GRL-08513 and GRL-08613, which have a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring and P2-tetrahydropyrano-tetrahydrofuran (Tp-THF) with a sulfonamide isostere, are potent against wild-type HIV-1 strains and multiple clinically isolated HIV-1 strains (50% effective concentration [EC50]: 0.0001 to ∼0.0032 μM). ABSTRACT To date, there are no specific treatment regimens for HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). Here, we report that two newly generated CNS-targeting HIV-1 protease (PR) inhibitors (PIs), GRL-08513 and GRL-08613, which have a P1-3,5-bis-fluorophenyl or P1-para-monofluorophenyl ring and P2-tetrahydropyrano-tetrahydrofuran (Tp-THF) with a sulfonamide isostere, are potent against wild-type HIV-1 strains and multiple clinically isolated HIV-1 strains (50% effective concentration [EC50]: 0.0001 to ∼0.0032 μM). As assessed with HIV-1 variants that had been selected in vitro to propagate at a 5 μM concentration of each HIV-1 PI (atazanavir, lopinavir, or amprenavir), GRL-08513 and GRL-08613 efficiently inhibited the replication of these highly PI-resistant variants (EC50: 0.003 to ∼0.006 μM). GRL-08513 and GRL-08613 also maintained their antiviral activities against HIV-2ROD as well as severely multidrug-resistant clinical HIV-1 variants. Additionally, when we assessed with the in vitro blood-brain barrier (BBB) reconstruction system, GRL-08513 and GRL-08613 showed the most promising properties of CNS penetration among the evaluated compounds, including the majority of FDA-approved combination antiretroviral therapy (cART) drugs. In the crystallographic analysis of compound-PR complexes, it was demonstrated that the Tp-THF rings at the P2 moiety of GRL-08513 and GRL-08613 form robust hydrogen bond interactions with the active site of HIV-1 PR. Furthermore, both the P1-3,5-bis-fluorophenyl- and P1-para-monofluorophenyl rings sustain greater contact surfaces and form stronger van der Waals interactions with PR than is the case with darunavir-PR complex. Taken together, these results strongly suggest that GRL-08513 and GRL-08613 have favorable features for patients infected with wild-type/multidrug-resistant HIV-1 strains and might serve as candidates for a preventive and/or therapeutic agent for HAND and other CNS complications.
Dose Reduction and Low-Contrast Detectability Using Iterative CBCT Reconstruction Algorithm for Radiotherapy

Introduction: Several studies have reported the relation between the imaging dose and secondary cancer risk and have emphasized the need to minimize the additional imaging dose as low as reasonably achievable. The iterative cone-beam computed tomography (iCBCT) algorithm can improve the image quality by utilizing scatter correction and statistical reconstruction. We investigate the use of a novel iCBCT reconstruction algorithm to reduce the patient dose while maintaining low-contrast detectability and registration accuracy. Methods: Catphan and anthropomorphic phantoms were analyzed. All CBCT images were acquired with varying dose levels and reconstructed with a Feldkamp–Davis–Kress algorithm-based CBCT (FDK-CBCT) and iCBCT. The low-contrast detectability was subjectively assessed using a 9-point scale by 4 reviewers and objectively assessed using structure similarity index (SSIM). The soft tissue-based registration error was analyzed for each dose level and reconstruction technique. Results: The results of subjective low-contrast detectability found that the iCBCT acquired at two-thirds of a dose was superior to the FDK-CBCT acquired at a full dose (6.4 vs 5.4). Relative to FDK-CBCT acquired at full dose, SSIM was higher for iCBCT acquired at one-sixth dose in head and head and neck region while equivalent with iCBCT acquired at two-thirds dose in pelvis region. The soft tissue-based registration was 2.2 and 0.6 mm for FDK-CBCT and iCBCT, respectively. Conclusion: Use of iCBCT reconstruction algorithm can generally reduce the patient dose by approximately two-thirds compared to conventional reconstruction methods while maintaining low-contrast detectability and accuracy of registration.
The Perception of Automation Reliability and Acceptance of Automated Advice

Objective Examine (1) the extent to which humans can accurately estimate automation reliability and calibrate to changes in reliability, and how this is impacted by the recent accuracy of automation; and (2) factors that impact the acceptance of automated advice, including true automation reliability, reliability perception, and the difference between an operator’s perception of automation reliability and perception of their own reliability. Background Existing evidence suggests humans can adapt to changes in automation reliability but generally underestimate reliability. Cognitive science indicates that humans heavily weight evidence from more recent experiences. Method Participants monitored the behavior of maritime vessels (contacts) in order to classify them, and then received advice from automation regarding classification. Participants were assigned to either an initially high (90%) or low (60%) automation reliability condition. After some time, reliability switched to 75% in both conditions. Results Participants initially underestimated automation reliability. After the change in true reliability, estimates in both conditions moved towards the common true reliability, but did not reach it. There were recency effects, with lower future reliability estimates immediately following incorrect automation advice. With lower initial reliability, automation acceptance rates tracked true reliability more closely than perceived reliability. A positive difference between participant assessments of the reliability of automation and their own reliability predicted greater automation acceptance. Conclusion Humans underestimate the reliability of automation, and we have demonstrated several critical factors that impact the perception of automation reliability and automation use. Application The findings have potential implications for training and adaptive human-automation teaming.
Developing mental health nursing strategies for the inbound quarantined population in China during the COVID-19 global pandemic.

OBJECTIVE The aim of the study was to develop mental health nursing strategies for the inbound quarantined population based on the results of a survey study and frontline nursing experiences. SUBJECTS AND METHODS A mixed research method was selected, we collected data by questionnaires from 128 quarantined people, and by semi-structured interviews from 5 registered nurses. Generalized anxiety disorder-7 (GAD-7), the patient health questionnaire-9 (PHQ-9), the Pittsburgh Sleep Quality Index (PSQI), Social Support Rating Scale (SSRS) were used in the quantitative research to identify the prevalence of psychological issues and risk factors. Semi-structured interviews were conducted in the qualitative study to conclude nursing experiences from RNs. RESULTS The overall prevalence of anxiety, depression, and insomnia were 34%, 41%, and 18% respectively. Binary logistic regression analysis showed that social support, urban residence, and chronic disease were associated with mental health problems in certain aspects. Three themes were emerged from the analysis of RNs interviews: personality, chronic diseases, and social support. CONCLUSIONS The prevalence of mental health issues in the inbound quarantined population was the same as the general population in the initial stage of COVID-19 outbreak, and significantly lower than people who lived in high-risk areas. Living in urban areas, with chronic diseases, and obtaining less social support are the risk factors. Finally, four nursing strategies were proposed by the research team for mental health well-being.
Design and Synthesis of Crosslinked Helix Dimers as Protein Tertiary Structure Mimics

Crosslinked helix dimers (CHDs) are synthetic tertiary helical structure motifs designed to modulate interactions of proteins with binding partners. Helix dimers serve as mimics of coiled coils, which are known to be implicated in a multitude of protein complexes. Coiled coils are typically stable in long peptides (>21‐28 residues), because sufficient intra‐ and interstrand contacts are not available in short peptides to coax strand assembly. To engineer conformationally stable CHDs in short sequences, we introduced a covalent linkage in place of an interhelical salt bridge and sculpted the helical interface with optimal hydrophobic packing. CHDs have shown efficacy for the disruption of targeted protein‐protein interactions in biochemical, cellular, and animal models. This article describes our optimized approach to design and synthesize parallel and antiparallel helical tertiary structure mimics. Synthesis of CHDs involves conjugation of individual peptide segments, purification of the mono‐conjugated strand, and alkylation of the two independent strands to yield crosslinked dimers. © 2022 Wiley Periodicals LLC.
Association of Essential Tremor With Novel Risk Loci

Key Points Question Can common genetic variants associated with essential tremor (ET) be identified? Findings In this genome-wide association study and meta-analysis including genetic data on 483 054 individuals, 5 genome-wide significant loci were associated with risk of ET and common variants were associated with approximately 18% of ET heritability. Meaning Findings of this study may help identify new genes and inform ET biology.
ACTG2 Variants in Pediatric Chronic Intestinal Pseudo-obstruction With Megacystis

Background/Aims Chronic intestinal pseudo-obstruction (CIPO) is a clinically heterogeneous syndrome characterized by compromised peristalsis and intestinal obstruction. Variants of actin gamma 2 (ACTG2), a protein crucial for correct enteric muscle contraction, have been found in CIPO patients. The aim of this study is to examine the clinical features and ACTG2 variants in Korean patients with CIPO. Methods From January 1995 to August 2020, 12 patients diagnosed with CIPO were included and genetic analysis testing of ACTG2 was performed. Results Heterozygous ACTG2 missense variants were found in 6 patients (50.0%). The p.Arg257Cys variant was found in 3 patients, and p.Arg63Gln and p.Arg178His variants were found in 1 patient each. A novel variant, p.Ile193Phe, was found in 1 patient. Three patients were diagnosed at birth, 2 at the age of 1 year, and 1 at 3 years of age. Abnormal prenatal genitourinary ultrasonographic findings were found in all 6 patients; microcolon was found in 4 patients (66.7%), and megacystis in all 6 patients. The pathology showed abnormal ganglion cells as well as myopathic findings. All patients are dependent on total parenteral nutrition and are to date alive. Conclusions ACTG2 variants are commonly found in Korean patients with CIPO. In CIPO patients with megacystis and abnormal prenatal ultrasonography, genetic testing of ACTG2 should be considered. Molecular diagnosis of CIPO is more important than pathologic diagnosis.
The distribution and pathogenic risk of non‐9‐valent vaccine covered HPV subtypes in cervical lesions

Human papillomavirus (HPV) infection is the main cause of female precancerous lesions and cervical cancer. The development and application of HPV prophylactic vaccines have been recognized as a major effective intervention for the control of cervical lesions. However, the infection rate and clinical characters of non‐9‐valent vaccine covered HPV subtypes are still worth studying. In this retrospective study, we included patients diagnosed and treated in the Department of Gynecology of Shanghai General Hospital between January 2017 and February 2021. The clinical features of non‐9‐valent vaccine covered HPV subtypes were explored in 2179 patients who have normal results, 338 patients with cervical intraepithelial neoplasia 1 (CIN1), and 153 patients with ≥CIN2. Univariate analysis showed that compared to the normal cervix group, age ≥50, pregnancy ≥5, delivery ≥3, menopause, no condom use, and cervical transformation zone type III were risk factors for CIN1 or ≥CIN2 (p < 0.05). Thirty‐one percent of CIN1 and 26% of ≥CIN2 were attributed to HPV51, HPV53, HPV56, and HPV68. Multivariate analysis revealed that HPV53, HPV81, age, menopause, cervical transformation area and involved glands were independent risk factors for ≥CIN2 group compared to the CIN1 group (p < 0.05). Additionally, among the 14 non‐9‐valent vaccine covered HPV subtypes, the infection rates of HPV53, 56, 51, and 68 were higher in this study. In conclusion, our study demonstrated the distribution and pathogenic risk of non‐9‐valent vaccine covered HPV subtypes in cervical lesions. These findings might supply a foundation for optimizing cervical cancer prevention in the post‐vaccine era.
Consequences of hyperandrogenemia during pregnancy in female offspring: attenuated response to angiotensin II

Background: Polycystic ovary syndrome (PCOS) is characterized by reproductive and metabolic dysfunction, and elevated blood pressure (BP). The cardiometabolic consequences of maternal hyperandrogenemia on offspring, either as adults or with aging, have not been well studied. We previously found that male offspring of hyperandrogenemic female (HAF) rats, a model of PCOS, are normotensive but have an exaggerated pressor response to angiotensin (Ang) II. Method: In this study, the hypothesis was tested that adult and aging female offspring of HAF rats develop a metabolic and hypertensive phenotype. Control and HAF rats were implanted prepubertally with placebo or dihydrotestosterone pellets, which continued throughout pregnancy and lactation. Results: Female offspring of HAF dams had lower birth weight than female control offspring. Although female HAF offspring (aged 16–24 weeks) had no differences in intrarenal Ang II, plasma lipids or proteinuria, they did have lower intrarenal Ang (1–7) and lower nitrate/nitrite excretion than controls. Adult HAF offspring had similar baseline BP as controls, but had an attenuated pressor response to Ang II. With aging (16–20 months), female HAF offspring remained normotensive with an attenuated pressor response to Ang II and high salt diet but more proteinuria and higher intrarenal Ang(1–7) than controls. Conclusion: Taken together, these data suggest that female HAF offspring are protected from developing hypertension, but may be at risk for renal injury with aging. Future studies are necessary to determine whether adult and postmenopausal offspring of PCOS women are at increased risk for cardiovascular dysfunction. Graphical abstract:http://links.lww. com/HJH/B820
Pain as a mediator in the temperament-alexithymia relationship in individuals suffering from rheumatoid arthritis.

OBJECTIVE The study aims to establish a relationship between temperament traits, symptoms of alexithymia, and pain intensity in rheumatoid arthritis. Despite the significant progress seen in the area of RA treatment, pain, often life-long, remains the predominant symptom. This constant pain and progressing disability, as well as dependence upon other people cause RA patients to experience psychological stress that can be modified by individual patient traits. Recently, several authors have underlined the need to relate personality and temperament constructs to neurobiological processes that may underlie individual differences. It seems then that patient characteristics may play a significant role in the course of the disease. PATIENTS AND METHODS The study was performed on a group of patients (N=317) with rheumatoid arthritis diagnosed according to the current criteria of the American-European Consensus of 2010. All patients expressed voluntary consent to participate, and the study protocol was approved by the Local Ethics Committee. This was a survey-based study. It involved the application of the adult version of the Buss and Plomin EAS Temperament Questionnaire (EAS-D), which tests 3 main temperament domains: sociability, activity, and emotionality. The pain was measured on the Visual Analogue Scale (VAS). VAS is used to measure pain intensity. The level of alexithymia was tested using the Toronto Alexithymia Scale-20. The scale consists of 20 statements and includes 3 subscales that measure difficulty in describing feelings/emotions, difficulty in identifying feelings/emotions, and operational externally oriented thinking. RESULTS The analysis revealed that alexithymia is positively correlated only with one dimension of temperament, i.e., emotionality, and with pain intensity. Moreover, high emotionality was positively correlated with pain. A simple mediation analysis revealed that pain intensity functioned as a mediator in the emotionality-alexithymia relationship. CONCLUSIONS The observed correlations indicate that RA patients with a high level of emotionality exhibit high alexithymia as they perceive pain related to the disease symptoms more intensely. The observed mediation is partial, meaning that there are also other mediating factors in this relationship.
Environmental relevant concentrations of triclosan affected developmental toxicity, oxidative stress, and apoptosis in zebrafish embryos

Triclosan (TCS), as a broad‐spectrum antibacterial agent, is widely used in various pharmaceutical and personal care products. However, the details of ecological environmental health risks of TCS are not clear. In this study, zebrafish embryos/larval were exposed to environmentally relevant concentrations of TCS to evaluate the developmental toxicity. Four‐hour post‐fertilization (hpf) zebrafish embryos were exposed to 0, 2, 10, 50, and 250 μg/L TCS until 96 h. The heart beats at 72 hpf were significantly increased in 2 μg/L TCS group, while significantly decreased in 250 μg/L TCS treated group compared with control. The results of acridine orange staining, terminal deoxynucleotide transferase‐mediated UTPnick end labeling assay, and detection of mitochondrial membrane potential showed that 50 and 250 μg/L TCS resulted in apoptosis. Meanwhile, reactive oxygen species (ROS) and DNA damage were induced, but SOD activity was significantly decreased in 250 μg/L TCS treated group. In addition, SOD(Mn) and GPx gene mRNA expressions were significantly down‐regulated in 50 and 250 μg/L TCS treated groups, while Casp3, Casp9, Puma, Casp8, Apaf1, and Bid genes in 250 μg/L TCS and Mdm2 gene in 50 μg/L treated groups were significantly up‐regulated. P53 protein was significantly up‐regulated in 250 μg/L TCS treated group. The overall results showed that TCS can cause oxidative stress and result in apoptosis via the involvement of ROS‐p53‐caspase‐dependent apoptotic pathway in zebrafish embryos. The present findings suggest the potential mechanisms of TCS‐induced developmental toxicity appears to be the generation of ROS and the consequent triggering of apoptosis genes.
A Course-Based Teaching Experience for STEM Undergraduates Improves Student Perceptions of Teaching Self-Efficacy and Attitudes Toward Teaching Careers

There is a national need to recruit more science teachers. Enhancing pathways to teaching for science, technology, engineering, and mathematics (STEM) majors could help to address this need. The Learn By Doing Lab is a course in which STEM undergraduates teach hands-on life science and physical science to local third- through eighth-grade schoolchildren visiting the campus. To measure the impacts of this teaching experience on the undergraduate participants, we administered a version of the Science Teaching Efficacy Belief Instrument-Preservice survey at the start and end of the course. Significant gains were observed in the students’ belief in their personal ability to effectively teach science (self-efficacy). Furthermore, qualitative and quantitative analysis of student reflections revealed that they perceived the Learn By Doing Lab experience to have helped them develop 21st-century competencies, particularly in the areas of collaboration, communication, and adaptability. Finally, the students’ overall awareness and positive perception of science teaching careers increased. This indicates that providing a low-barrier course-based teaching experience for STEM undergraduates is a promising strategy to help recruit pre-service teachers, and a step toward alleviating the national STEM teacher shortage.
Vacuolar (H+ )-ATPase subunit c is essential for the survival and systemic RNA interference response in Locusta migratoria.

BACKGROUND Vacuolar (H+ )-ATPase (V-ATPase) is a multi-subunit enzyme that hydrolyzes ATP to transport protons across a cellular membrane, and it plays an important role in numerous biological processes, including in growth, development and immune responses. The c subunit of V-ATPase is a highly conserved subunit of the rotatory proteolipid ring that is required for binding and transporting protons. To date, there are only a few published reports on V-ATPase-c functions in insects. RESULTS We identified and characterized the V-ATPase-c gene in Locusta migratoria, one of the most destructive agricultural insect pests in the world. LmV-ATPase-c was predominately expressed in Malpighian tubules of nymphs, followed by the hindgut and ovary, while the other tissues showed relatively low expression levels. Silencing of LmV-ATPase-c caused severe molting defects in nymphs and a high mortality rate of >90%. Histological staining and microscopic examination of sections from the abdominal cuticle revealed the absence of newly formed cuticle in nymphs that were injected with dsLmV-ATPase-c. In addition, silencing of LmV-ATPase-c transcript levels significantly impaired RNA interference (RNAi) efficiency of a reporter gene. By quantifying double stranded RNA (dsRNA) amounts by quantitative PCR, we found that RNAi against LmV-ATPase-c provoked a dramatic accumulation of dsRNA in the endosomes of epidermal and midgut cells of L. migratoria. CONCLUSION Our results indicate that LmV-ATPase-c is indispensable for the formation of new cuticle during the molting process and has pivotal functions in dsRNA escape from endosomes. LmV-ATPase-c might be a valuable target for developing new strategies for insect pest management.
The many facets of shape

Shape is an interesting property of objects because it is used in ordinary discourse in ways that seem to have little connection to how it is typically defined in mathematics. The present article describes how the concept of shape can be grounded within Euclidean and non-Euclidean geometry and also to human perception. It considers the formal methods that have been proposed for measuring the differences among shapes and how the performance of those methods compares with shape difference thresholds of human observers. It discusses how different types of shape change can be perceptually categorized. It also evaluates the specific data structures that have been used to represent shape in models of both human and machine vision, and it reviews the psychophysical evidence about the extent to which those models are consistent with human perception. Based on this review of the literature, we argue that shape is not one thing but rather a collection of many object attributes, some of which are more perceptually salient than others. Because the relative importance of these attributes can be context dependent, there is no obvious single definition of shape that is universally applicable in all situations.