Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-Acting BMS-378806 Analogues Stabilize the State-1 Conformation of the Human Immunodeficiency Virus Type 1 Envelope Glycoproteins

The envelope glycoprotein (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) mediates the entry of the virus into host cells and is also the target for antibodies. During virus entry, Env needs to change shape. Env flexibility also contributes to the ability of HIV-1 to evade the host immune response; many shapes of Env raise antibodies that cannot recognize the functional Env and therefore do not block virus infection. We found that an HIV-1 entry inhibitor, BMS-806, stabilizes the functional shape of Env. We developed new variants of BMS-806 that stabilize Env in its natural state for long periods of time. The availability of such long-acting stabilizers of Env shape will allow the natural Env conformation to be characterized and tested for efficacy as a vaccine. ABSTRACT During human immunodeficiency virus type 1 (HIV-1) entry into cells, the viral envelope glycoprotein (Env) trimer [(gp120/gp41)3] binds the receptors CD4 and CCR5 and fuses the viral and cell membranes. CD4 binding changes Env from a pretriggered (state-1) conformation to more open downstream conformations. BMS-378806 (here called BMS-806) blocks CD4-induced conformational changes in Env important for entry and is hypothesized to stabilize a state-1-like Env conformation, a key vaccine target. Here, we evaluated the effects of BMS-806 on the conformation of Env on the surface of cells and virus-like particles. BMS-806 strengthened the labile, noncovalent interaction of gp120 with the Env trimer, enhanced or maintained the binding of most broadly neutralizing antibodies, and decreased the binding of poorly neutralizing antibodies. Thus, in the presence of BMS-806, the cleaved Env on the surface of cells and virus-like particles exhibits an antigenic profile consistent with a state-1 conformation. We designed novel BMS-806 analogues that stabilized the Env conformation for several weeks after a single application. These long-acting BMS-806 analogues may facilitate enrichment of the metastable state-1 Env conformation for structural characterization and presentation to the immune system. IMPORTANCE The envelope glycoprotein (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) mediates the entry of the virus into host cells and is also the target for antibodies. During virus entry, Env needs to change shape. Env flexibility also contributes to the ability of HIV-1 to evade the host immune response; many shapes of Env raise antibodies that cannot recognize the functional Env and therefore do not block virus infection. We found that an HIV-1 entry inhibitor, BMS-806, stabilizes the functional shape of Env. We developed new variants of BMS-806 that stabilize Env in its natural state for long periods of time. The availability of such long-acting stabilizers of Env shape will allow the natural Env conformation to be characterized and tested for efficacy as a vaccine.
Effect of dapagliflozin alone and in combination with insulin in a rat model of type 1 diabetes

Dapagliﬂozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor; it reduces glucose reabsorption via the kidney and increases the glucose excretion in urine. This inhibitor functions through a unique insulin-independent mechanism, and is therefore a potential new approach for the treatment of hyperglycemia in patients with diabetes. In this study, we evaluated the effectiveness of the SGLT2 inhibitor, dapagliflozin, by using a rat model of type 1 diabetes. Type 1 diabetes was induced by a single intraperitoneal injection of 60 mg/kg streptozotocin (STZ). The STZ-induced rats showed marked hyperglycemia and other metabolic abnormalities. We clarified the hypoglycemic effect of the combination treatment of dapagliflozin with a low dose of insulin compared with dapagliflozin alone and insulin alone in 3-week and 8-week studies. Our results showed that dapagliflozin in combination with a low dose of insulin significantly lowered hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. Furthermore, the antioxidant status and body weight were improved. In contrast, treatment with dapagliflozin alone did not improve the blood glucose levels, lipid profile, antioxidant status, or body weight. These findings suggested that in type 1 diabetes, dapagliflozin was effective in combination with a low dose of insulin; however, the administration of dapagliflozin alone did not achieve a significant effect.
Allosteric p97 Inhibitors Can Overcome Resistance to ATP‐Competitive p97 Inhibitors for Potential Anticancer Therapy

Abstract: A major challenge of targeted cancer therapy is the selection for drug‐resistant mutations in tumor cells leading to loss of treatment effectiveness. p97/VCP is central regulator of protein homeostasis and a promising anticancer target because of its vital role in cell growth and survival. One ATP‐competitive p97 inhibitor, CB‐5083, has entered clinical trials. Selective pressure on HCT116 cells dosed with CB‐5083 identified five different resistant mutants. Identification of p97 inhibitors with different mechanisms of action would offer the potential to overcome this class of resistance mutations. Our results demonstrate that two CB‐5083 resistant p97 mutants, N660 K and T688 A, were also resistant to several other ATP‐competitive p97 inhibitors, whereas inhibition by two allosteric p97 inhibitors NMS‐873 and UPCDC‐30245 were unaffected by these mutations. We also established a CB‐5083 resistant cell line that harbors a new p97 double mutation (D649 A/T688 A). While CB‐5083, NMS‐873, and UPCDC‐30245 all effectively inhibited proliferation of the parental HCT116 cell line, NMS‐873 and UPCDC‐30245 were 30‐fold more potent in inhibiting the CB‐5083 resistant D649 A/T688 A double mutant than CB‐5083. Our results suggest that allosteric p97 inhibitors are promising alternatives when resistance to ATP‐competitive p97 inhibitors arises during anticancer treatment.
Biology and Clinical Application of Regulatory RNAs in Hepatocellular Carcinoma

Most of the human genome consists of DNA genes that are translated into RNAs but not into proteins. These RNA molecules are named noncoding RNAs (ncRNA). While in the past it was thought that ncRNAs would be redundant without relevant functions, it is now well established that ncRNAs identify a class of regulatory molecules that finely tune cell homeostasis and are deregulated in disease states, including hepatocellular carcinoma (HCC). Of note, the number of ncRNAs within a cell increases progressively, with the complexity of the species indicating their essential role in the maintenance of regulatory networks that affect the intricacy of the organism. ncRNAs have been demonstrated to mediate HCC development and progression by affecting intrinsic cancer cell signaling and crosstalk between malignant cells and the microenvironment. Moreover, ncRNAs hold promise as clinical biomarkers, but further evidence is warranted before their translation and integration within clinical practice.
Iodine status of breastfed infants and their mothers' breast milk iodine concentration

Abstract Iodine is an essential nutrient for growth and development during infancy. Data on iodine status of exclusively (EBF) and partially breastfed (PBF) infants as well as breast milk iodine concentration (BMIC) are scarce. We aimed to assess (a) infant iodine nutrition at the age of 5.5 months by measuring urinary iodine concentration (UIC) in EBF (n = 32) and PBF (n = 28) infants and (b) mothers' breast milk iodine concentration (n = 57). Sixty mother–infant pairs from three primary health care centres in Reykjavik and vicinities provided urine and breast milk samples for iodine analysis and information on mothers' habitual diet. The mother–infant pairs were participants of the IceAge2 study, which focuses on factors contributing to infant growth and development, including body composition and breast‐milk energy content. The median (25th–75th percentiles) UIC was 152 (79–239) μg/L, with no significant difference between EBF and PBF infants. The estimated median iodine intake ranged from 52 to 86 μg/day, based on urinary data (assuming an average urine volume of 300–500 ml/day and UIC from the present study). The median (25th–75th percentiles) BMIC was 84 (48–114) μg/L. It is difficult to conclude whether iodine status is adequate in the present study, as no ranges for median UIC reflecting optimal iodine nutrition exist for infants. However, the results add important information to the relatively sparse literature on UIC, BMIC, and iodine intake of breastfed infants.
The radiotherapy cancer patient: female inclusive, but male dominated

Abstract Background: The sex-neutral language used in preclinical and clinical research intends to be inclusive of both the female and the male population, but the practice of data pooling prevents the detection of the impact of sex on cancer biology and response to medications and treatment. This study aimed to examine the consideration of sex as biological variable in the evaluation of radiation therapy in preclinical and clinical studies. Methods: Preclinical and clinical studies published over a 12-month period were reviewed for the reporting of cells, animal or patient sex and the inclusion of sex as a biological variable in both study design and data analysis. Results: A total of 321 articles met the inclusion criteria: 41 (13%) preclinical and 280 (87%) clinical studies. Two articles reported separate outcome data for males and females. Where the sex of participants was stated (230/280 (82%), 81% reported a larger number of male participants, compared to females. Less than half (45%) of studies used sex as a variable in data analysis. Sex disparity was not dependent on study location but may be more prominent in certain cancer sites. In preclinical studies, sex was at best stated in those reporting on animals (48% of studies). Conclusion: Referring to a radiotherapy cancer patient, the literature is female inclusive, but a gap does exist when it comes to consideration of sex in data analysis. The pooled analysis of female and male data could introduce statistical biases and prevent the identification of key sex-specific biological subtilities that do affect radiation responses.
Using ggtree to Visualize Data on Tree‐Like Structures

Ggtree is an R/Bioconductor package for visualizing tree‐like structures and associated data. After 5 years of continual development, ggtree has been evolved as a package suite that contains treeio for tree data input and output, tidytree for tree data manipulation, and ggtree for tree data visualization. Ggtree was originally designed to work with phylogenetic trees, and has been expanded to support other tree‐like structures, which extends the application of ggtree to present tree data in other disciplines. This article contains five basic protocols describing how to visualize trees using the grammar of graphics syntax, how to visualize hierarchical clustering results with associated data, how to estimate bootstrap values and visualize the values on the tree, how to estimate continuous and discrete ancestral traits and visualize ancestral states on the tree, and how to visualize a multiple sequence alignment with a phylogenetic tree. The ggtree package is freely available at https://www.bioconductor. org/packages/ggtree. © 2020 by John Wiley & Sons, Inc.
Neural characteristics of cognitive reappraisal success and failure: An ERP study

Cognitive reappraisal, an important strategy of emotion regulation, can change emotional experience and attention to emotional information. However, not all individuals can deploy reappraisal strategies successfully. In the current study, we investigated event‐related potential (ERP) characteristics of reappraisal success and of reappraisal failure.
Aspirin and the chemoprevention of cancers: A mathematical and evolutionary dynamics perspective

Epidemiological data indicate that long‐term low dose aspirin administration has a protective effect against the occurrence of colorectal cancer, both in sporadic and in hereditary forms of the disease. The mechanisms underlying this protective effect, however, are incompletely understood. The molecular events that lead to protection have been partly defined, but remain to be fully characterized. So far, however, approaches based on evolutionary dynamics have not been discussed much, but can potentially offer important insights. The aim of this review is to highlight this line of investigation and the results that have been obtained. A core observation in this respect is that aspirin has a direct negative impact on the growth dynamics of the cells, by influencing the kinetics of tumor cell division and death. We discuss the application of mathematical models to experimental data to quantify these parameter changes. We then describe further mathematical models that have been used to explore how these aspirin‐mediated changes in kinetic parameters influence the probability of successful colony growth versus extinction, and how they affect the evolution of the tumor during aspirin administration. Finally, we discuss mathematical models that have been used to investigate the selective forces that can lead to the rise of mismatch‐repair deficient cells in an inflammatory environment, and how this selection can be potentially altered through aspirin‐mediated interventions.
Long‐term follow‐up of the randomized trial of mesorectal excision with or without lateral lymph node dissection in rectal cancer (JCOG0212)

Japan Clinical Oncology Group (JCOG) 0212 (ClinicalTrials.gov NCT00190541) was a non‐inferiority phase III trial of patients with clinical stage II–III rectal cancer without lateral pelvic lymph node enlargement. The trial compared mesorectal excision (ME) with ME and lateral lymph node dissection (LLND), with a primary endpoint of recurrence‐free survival (RFS). The planned primary analysis at 5 years failed to confirm the non‐inferiority of ME alone compared with ME and LLND. The present study aimed to compare ME alone and ME with LLND using long‐term follow‐up data from JCOG0212.
Associations between sensitivity to antibiotics, disinfectants and heavy metals in natural, clinical and laboratory isolates of Escherichia coli

Summary Bacteria in nature often encounter non‐antibiotic antibacterials (NAAs), such as disinfectants and heavy metals, and they can evolve resistance via mechanisms that are also involved in antibiotic resistance. Understanding whether susceptibility to different types of antibacterials is non‐randomly associated across natural and clinical bacteria is therefore important for predicting the spread of resistance, yet there is no consensus about the extent of such associations or underlying mechanisms. We tested for associations between susceptibility phenotypes of 93 natural and clinical Escherichia coli isolates to various NAAs and antibiotics. Across all compound combinations, we detected a small number of non‐random associations, including a trio of positive associations among chloramphenicol, triclosan and benzalkonium chloride. We investigated genetic mechanisms that can explain such associations using genomic information, genetic knockouts and experimental evolution. This revealed some mutations that are selected for by experimental exposure to one compound and confer cross‐resistance to other compounds. Surprisingly, these interactions were asymmetric: selection for chloramphenicol resistance conferred cross‐resistance to triclosan and benzalkonium chloride, but selection for triclosan resistance did not confer cross‐resistance to other compounds. These results identify genetic changes involved in variable cross‐resistance across antibiotics and NAAs, potentially contributing to associations in natural and clinical bacteria.
Explaining Individual Differences in Colorectal Cancer Screening Preferences: Analysis and Meta-analysis of Discrete Choice Experiments

Colorectal cancer (CRC) is the second leading cause of cancer related death in the U.S. among men and women combined. In addition to the personal toll it takes, CRC is estimated to cost billions of dollars annually in medical costs. Due to the high rates and costs of CRC, a significant public health effort has been made to promote participation in screening, which has been shown to be effective at reducing CRC incidence and mortality rates; however, despite efforts to promote screening and research showing its effectiveness, screening rates remain low. Approaches to increasing screening participation focus on understanding the decision-making process people go through regarding screening. Health economics and health psychology provide two unique approaches to understanding this decision-making process. Health economics approaches model screening behavior as a function of the screening characteristics themselves while health psychology approaches model screening behavior as a function of individual factors related to perceptions and beliefs. This dissertation set out to explain individual differences in screening preferences using both health economics and health psychology approaches. This dissertation utilized three different methods, including a systematic review and meta-analysis, a latent class analysis of discrete choice data, and a discrete choice experiment (DCE) that included psychological factors as characteristics of the screening process. We found evidence to support the hypothesis that differences in screening preferences exist and that individual factors like socio-demographic and psychological factors may play a role in explaining these differences. We also found evidence to support the validity of including psychological factors as attributes that vary in a DCE. This dissertation discusses the implications of the findings for theory, research, and the development of future screening programs.
Sex Differences in Stroke Rehabilitation Care in Alberta

ABSTRACT: Background: Female stroke patients may experience poorer functional outcomes than males following inpatient rehabilitation. Methods: Data from Alberta inpatient stroke rehabilitation units were examined to determine: (1) the impact of sex on time to inpatient rehabilitation, functional gains (using the Functional Independence Measure (FIM)), length of stay (LOS), and discharge destination; (2) if sex was related to age at the time of stroke, stroke severity, and living arrangement at discharge from rehabilitation; and (3) whether patients’ age and preadmission living arrangement had an influence on LOS in rehabilitation or discharge destination. Results: Two thousand two hundred sixty-six adult stroke patients (1283 males and 983 females) were subcategorized as mild (FIM >80; n = 1155), moderate (FIM 40–80; n = 994), or severe (FIM <40; n = 117). Fifty-five percent of males (45.7% females) had mild stroke; 39.5% of males (49.5% females) had moderate stroke; and 5.5% of males (4.8% females) had severe stroke. Females were significantly older than males (p = 2.4 × 10−4). No sex difference existed in time from acute care to rehabilitation admission (p = 0.73) or in mean FIM change (p = 0.294). Mean LOS was longer for females than males (p=0.018). Males were more likely than females to be discharged home (p = 1.8 × 10−13). Further, male patients (p = 6.4 × 10−7) and those < 65 years (p = 1.4 × 10−23) were more likely to be discharged home without homecare. Conclusion: There are significant sex and age differences in LOS in rehabilitation and discharge destination of stroke patients. These differences may suggest that sex and age of the patient need to be considered in care planning.
The Effect of Viscosity and Application Mode of Phosphoric Acid on Bond Strength of GlassFiber Post

Background When a phosphoric acid is used, before applying an adhesive system, it is known that obtaining an effective adhesion to the root canal walls is a challenge. The aim of the present study was to evaluate the influence of phosphoric acid viscosity and application mode on the push-out bond strength (BS) values of fiberglass post to root dentin. The conditioning pattern on the root dentin was also evaluated. Materials and Methods The roots of 44 endodontically treated premolars were divided into 4 groups, of eleven teeth each, according to the combination of the main factors: phosphoric acid viscosity (liquid or gel) and application mode (passive or sonic). After application of the two-step etch-and-rinse adhesive system, the fiberglass posts were cemented with a dual-cure resin-cement. Roots were sectioned transversely into six 1-mm slices for push-out BS test at 0.5 mm/min. Some roots of each group were selected for evaluation of the conditioning pattern by scanning electron microscopy. BS results (three-way ANOVA and Tukey’s test) and the conditioning pattern (Kruskal–Wallis test and Mann–Whitney test) were statistically evaluated (α= 0.05). Results The highest BS value was observed with a liquid phosphoric acid under sonic application mode (p < 0.05), being all other groups similar to one another (p < 0.05). Also, the highest BS value was observed in the cervical third, followed by the medium and the apical thirds (p < 0.05). The sonic application produced better smear layer removal and opening of dentinal tubules for both viscosities (p = 0.015). Conclusion A better bonding of fiberglass posts to root canals can be achieved when the post spaces are conditioned with a liquid phosphoric acid under sonic application.
The illicit cigarette market in six South African townships.

BACKGROUND We estimate the size of the illicit cigarette market in low socioeconomic areas in South Africa before and after a tax increase. In 2018, the real excise tax increased by 3% and the value-added tax (VAT) rate increased from 14% to 15%. Thus, the real tax on cigarettes increased by 4%. METHODS A total of 2427 smokers were interviewed over two rounds of data collection (1234 before the tax increase and 1193 after). Data were collected in six townships across four of South Africa's nine provinces. Smokers were asked about their most recent cigarette purchase. Cigarettes purchased for R1 (US$0.08) or less per stick are presumed illicit, based on a threshold price, which includes production costs and taxes. RESULTS In 2017 and 2018 respectively, 34.6% and 36.4% of smokers in the sample purchased illicit cigarettes. The increase in the proportion of illicit purchases was not statistically significant. Smokers with relatively low socioeconomic status, those who have low levels of education and those who are older or unemployed are most likely to purchase illicit cigarettes. CONCLUSIONS The illicit cigarette trade in South African townships is widespread. The government should implement an independent track and trace system to curb tax evasion. This would reduce the availability of illicit cigarettes, improve public health and increase excise tax collection.