Miracle-dz/UniFAR-FTUs huggingface dataset:
Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design

Ergosterol biosynthesis pathways essential to pathogenic protozoa growth and absent from the human host offer new chokepoint targets. Here, we present characterization and cell-based interference of Acanthamoeba spp sterol 24-/28-methylases (SMTs) that catalyze the committed step in C28- and C29-sterol synthesis. Intriguingly, our kinetic analyses suggest that 24-SMT prefers plant cycloartenol whereas 28-SMT prefers 24(28)-methylene lophenol in similar fashion to the substrate preferences of land plant SMT1 and SMT2. Transition state analog-24(R,S),25-epiminolanosterol (EL) and suicide substrate 26,27-dehydrolanosterol (DHL) differentially inhibited trophozoite growth with IC50 values of 7 nM and 6 µM, respectively, and EL yielded 20-fold higher activity than reference drug voriconazole. Against either SMT assayed with native substrate, EL exhibited tight binding ∼Ki 9 nM. Alternatively, DHL is methylated at C26 by 24-SMT that thereby, generates intermediates that complex and inactivate the enzyme, whereas DHL is not productively bound to 28-SMT. Steroidal inhibitors had no effect on human epithelial kidney cell growth or cholesterol biosynthesis at minimum amoebicidal concentrations. We hypothesize the selective inhibition of Acanthamoeba by steroidal inhibitors representing distinct chemotypes may be an efficient strategy for the development of promising compounds to combat amoeba diseases.
N-Glycosylation regulates endothelial lipase-mediated phospholipid hydrolysis in apoE- and apoA-I-containing high density lipoproteins Published, JLR Papers in Press, June 3, 2007.

Endothelial lipase (EL) is a member of the triglyceride lipase gene family with high phospholipase and low triacylglycerol lipase activities and a distinct preference for hydrolyzing phospholipids in HDL. EL has five potential N-glycosylation sites, four of which are glycosylated. The aim of this study was to determine how glycosylation affects the phospholipase activity of EL in physiologically relevant substrates. Site-directed mutants of EL were generated by replacing asparagine (N) 62, 118, 375, and 473 with alanine (A). These glycan-deficient mutants were used to investigate the kinetics of phospholipid hydrolysis in fully characterized preparations of spherical reconstituted high density lipoprotein (rHDL) containing apolipoprotein E2 (apoE2) [(E2)rHDL], apoE3 [(E3)rHDL], apoE4 [(E4)rHDL], or apoA-I [(A-I)rHDL] as the sole apolipoprotein. Wild-type EL hydrolyzed the phospholipids in (A-I)rHDL, (E2)rHDL, (E3)rHDL, and (E4)rHDL to similar extents. The phospholipase activities of EL N118A, EL N375A, and EL N473A were significantly diminished relative to that of wild-type EL, with the greatest reduction being apparent for (E3)rHDL. The phospholipase activity of EL N62A was increased up to 6-fold relative to that of wild-type EL, with the greatest enhancement of activity being observed for (E2)rHDL. These data show that individual N-linked glycans have unique and important effects on the phospholipase activity and substrate specificity of EL.
Socio-Cultural Factors Associated with Antenatal Services Utilization: A Cross-Sectional Study in Eastern Nepal

Background: This study was done to assess the socio-economic factors associated with Antenatal care (ANC) service utilization in Eastern Nepal. Methods: A cross-sectional quantitative study was conducted in Sunsari district of Eastern Nepal. A total of 372 Women delivered within period of one year preceding and this study were interviewed through household visit. Results: Logistic regression analyses revealed that women exposed to media had more than three times higher chance of receiving four or more ANC services (AOR=3.48, 95%CI:1.20-10.05). Similarly, women from advantaged ethnicity had more than two times higher chance of having four or more ANC visits than respondents who were from disadvantaged ethnicity (AOR=2.43, 95%CI: 2.04-6.92). Similarly, women having higher level of autonomy were nearly three times more likely to have four or more ANC visits than the women having lower level of autonomy (AOR= 2.86, 95%CI: 1.47-5.64)). Similarly richer women were two times more likely to have four or more ANC visits than poorer women (AOR=2.28, 95%CI: 1.06-5.25). Conclusion: Relatively advantaged ethnicity, higher rank of women's autonomy, good knowledge on maternal health service and knowledge on incentive upon completion of ANC, media exposure with maternal health service related massages and higher wealth rank were found significantly associated with 4 time ANC service utilization.
Proceduralisation, choice and parental reflections on decisions to accept newborn bloodspot screening

Newborn screening is the programme through which newborn babies are screened for a variety of conditions shortly after birth. Programmes such as this are individually oriented but resemble traditional public health programmes because they are targeted at large groups of the population and they are offered as preventive interventions to a population considered healthy. As such, an ethical tension exists between the goals of promoting the high uptake of supposedly ‘effective’ population-oriented programmes and the goal of promoting genuinely informed decision-making. There is, however, a lack of understanding with regard to how parents experience the tension between promoting uptake and facilitating informed choice. This paper addresses this issue, and data are presented to show how aspects of the timing, presentation of information and procedural routinisation of newborn screening serves to impact on the decisions made by parents.
Findings from a Delphi exercise regarding conflicts of interests, general practitioners and safeguarding children: ‘Listen carefully, judge slowly’

General practitioners (GPs) have to negotiate a range of challenges when they suspect child abuse or neglect. This article details findings from a Delphi exercise that was part of a larger study exploring the conflicts of interest that arise for UK GPs in safeguarding children. The specific objectives of the Delphi exercise were to understand how these conflicts of interest are seen from the perspectives of an expert panel, and to identify best practice for GPs. The Delphi exercise involved four iterative rounds with questionnaires completed by an expert panel. Results from each round were distilled and findings sent to panel members until consensus was reached. Panel members shared insights regarding their understanding of conflicts of interest in relation to GPs and safeguarding children and responses when conflicts of interests arise. Findings suggested a broader understanding of conflicts of interest (intrapersonal, interpersonal, interprofessional and interagency), the importance of professional judgement in uncertain situations when both action and inaction have potentially negative consequences and the importance of trust. The Delphi exercise was an effective means to bring together a wide range of professional and disciplinary perspectives on a complex topic. Findings caution against the oversimplification of the conceptual and practical issues, emphasise the importance of professional judgement, and support the development of open and trusting relationships with families and among professionals in health and social care agencies.
Cholesterol esterification and atherogenic index of plasma correlate with lipoprotein size and findings on coronary angiography

We examined the association between rate of cholesterol esterification in plasma depleted of apolipoprotein B-containing lipoproteins (FERHDL), atherogenic index of plasma (AIP) [(log (TG/HDL-C)], concentrations, and size of lipoproteins and changes in coronary artery stenosis in participants in the HDL-Atherosclerosis Treatment Study. A total of 160 patients was treated with simvastatin (S), niacin (N), antioxidants (A) and placebo (P) in four regimens. FERHDL was measured using a radioassay; the size and concentration of lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. The S+N and S+N+A therapy decreased AIP and FERHDL, reduced total VLDL (mostly the large and medium size particles), decreased total LDL particles (mostly the small size), and increased total HDL particles (mostly the large size). FERHDL and AIP correlated negatively with particle sizes of HDL and LDL, positively with VLDL particle size, and closely with each other (r = 0.729). Changes in the proportions of small and large lipoprotein particles, which were reflected by FERHDL and AIP, corresponded with findings on coronary angiography. Logistic regression analysis of the changes in the coronary stenosis showed that probability of progression was best explained by FERHDL (P = 0.005). FERHDL and AIP reflect the actual composition of the lipoprotein spectrum and thus predict both the cardiovascular risk and effectiveness of therapy. AIP is already available for use in clinical practice as it can be readily calculated from the routine lipid profile.
Reconstituted high-density lipoprotein infusion modulates fatty acid metabolism in patients with type 2 diabetes mellitus

We recently demonstrated that reconstituted high-density lipoprotein (rHDL) modulates glucose metabolism in humans via both AMP-activated protein kinase (AMPK) in muscle and by increasing plasma insulin. Given the key roles of both AMPK and insulin in fatty acid metabolism, the current study investigated the effect of rHDL infusion on fatty acid oxidation and lipolysis. Thirteen patients with type 2 diabetes received separate infusions of rHDL and placebo in a randomized, cross-over study. Fatty acid metabolism was assessed using steady-state tracer methodology, and plasma lipids were measured by mass spectrometry (lipidomics). In vitro studies were undertaken in 3T3-L1 adipocytes. rHDL infusion inhibited fasting-induced lipolysis (P = 0.03), fatty acid oxidation (P < 0.01), and circulating glycerol (P = 0.04). In vitro, HDL inhibited adipocyte lipolysis in part via activation of AMPK, providing a possible mechanistic link for the apparent reductions in lipolysis observed in vivo. In contrast, circulating NEFA increased after rHDL infusion (P < 0.01). Lipidomic analyses implicated phospholipase hydrolysis of rHDL-associated phosphatidylcholine as the cause, rather than lipolysis of endogenous fat stores. rHDL infusion inhibits fasting-induced lipolysis and oxidation in patients with type 2 diabetes, potentially through both AMPK activation in adipose tissue and elevation of plasma insulin. The phospholipid component of rHDL also has the potentially undesirable effect of increasing circulating NEFA.
Behavioral Interventions for Infant Immunizations

Minimal research has examined behavioral interventions to reduce infants' pain. This study randomly assigned 123 infants receiving immunizations and their parents to a condition: distraction (parents used stimuli to divert infants' attention), supportive care (parents were encouraged to utilize any coping-promoting strategies), or typical care. Infants in the supportive care condition recovered from the immunization significantly faster than did infants in the typical care condition, and parents in the distraction condition used significantly more behavioral interventions throughout the immunization than the other conditions. Given the apparent ineffectiveness of distracter stimuli despite parents' efforts, distracter options are discussed.
Signed area of sectors between spline curves and the origin

Formulas for representing the signed area of sectors between Bezier and B-spline curve segments and the origin are presented. The area is expressed by using the coordinates of the control points and coefficients calculated with the basis functions of the spline curves. Area-preserving deformations of the spline curves by moving the control points are also investigated.
Life experience: A neglected form of knowledge in social work education and practice

Abstract The significance of ‘life experience’ for career choice has emerged as a key finding in our study of social work students at a British university. This article analyses those ‘life experiences’ which students identify as influencing their decision to become social workers. The findings raise questions about the status of ‘life experience’ as a form of knowledge in social work. They also point to the complex relationships between ‘life experiences’ and motivations to pursue a social work career. It is argued that ‘life experiences’ significantly influence social work practice and education, and although often overlooked, they provide a potentially valuable resource for promoting professional practice.
Lipidomic changes of LDL in overweight and moderately hypercholesterolemic subjects taking phytosterol- and omega-3-supplemented milk[S]

The benefits of dietary phytosterols (PhySs) and long-chain n-3 PUFA (ω3) have been linked to their effects as cholesterol- and triglyceride (TGL)-lowering agents. However, it remains unknown whether these compounds have further metabolic effects on LDL lipid composition. Here, we studied the effects of PhyS- or ω3-supplemented low-fat milk (milk) on the LDL-lipidome. Overweight and moderately hypercholesterolemic subjects (n = 32) were enrolled in a two-arm longitudinal crossover study. Milk (250 ml/day), enriched with either 1.57 g PhyS or 375 mg ω3 (EPA + DHA), was given to the participants during two sequential 28 day intervention periods. Compared with baseline, PhyS-milk induced a higher reduction in the LDL cholesterol (LDLc) level than ω3-milk. LDL resistance to oxidation was significantly increased after intervention with PhyS-milk. Changes in TGL and VLDL cholesterol were only evident after ω3-milk intake. Lipidomic analysis revealed a differential effect of the PhyS- and ω3-milk interventions on the LDL lipid metabolite pattern. Content in LDL-glycerophospholipids was reduced after PhyS-milk intake, with major changes in phosphatidylcholine (PC) and phosphatidylserine subclasses, whereas ω3-milk induced significant changes in the long-chain polyunsaturated cholesteryl esters and in the ratio PC36:5/lysoPC16:0, associated to a reduced inflammatory activity. In conclusion, daily intake of milk products containing PhyS or ω3 supplements induce changes in the LDL-lipidome that indicate reduced inflammatory and atherogenic effects, beyond their LDLc- and TGL-lowering effects.
Associations of anthropometry and lifestyle factors with HDL subspecies according to apolipoprotein C-III[S]

The presence of apoC-III on HDL impairs HDL’s inverse association with coronary heart disease (CHD). Little is known about modifiable factors explaining variation in HDL subspecies defined according to apoC-III. The aim was to investigate cross-sectional associations of anthropometry and lifestyle with HDL subspecies in 3,631 participants from the Diet, Cancer, and Health study originally selected for a case-cohort study (36% women; age 50–65 years) who were all free of CHD. Greater adiposity and less activity were associated with higher HDL containing apoC-III and lower HDL lacking apoC-III. Per each 15 cm higher waist circumference, the level of HDL containing apoC-III was 2.8% higher (95% CI: 0.4, 5.3; P = 0.024) and the level of HDL not containing apoC-III was 4.7% lower (95% CI: −6.0, −3.4; P = <0.0001). Associations for physical activity were most robust to multivariable modeling. Each 20 metabolic equivalent task hours per week reported higher physical activity was associated with 0.9% (95% CI: −1.7, −0.1; P = 0.031) lower HDL containing apoC-III and 0.5% higher (95% CI: 0.1, 1.0; P = 0.029) HDL lacking apoC-III. Lower alcohol consumption was associated with lower HDL lacking apoC-III (percent difference per 15 g/day: 1.58 (95% CI: 0.84, 2.32; P = <0.0001). Adiposity and sedentary lifestyle were associated with a less favorable HDL subspecies profile.
Microsurgical varicocelectomy for clinical varicocele: A review for potential new indications

Microsurgical varicocelectomy is considered the gold‐standard technique treating varicocele in both adults and adolescents, due to relatively more favourable outcomes and lower post‐operative recurrence and complication rates. Despite of mounting literature on this topic, several aspects are still not well defined. We summarised the most recent literature and presented findings that might extend its indications. Microsurgical varicocelectomy and intracytoplasmic sperm injection are both effective to father a child for infertile men with clinical varicocele even for those with worst condition of spermatozoa, nonobstructive azoospermia, and prior varicocele repair has substantial benefits for couples with a clinical varicocele. Microsurgical subinguinal and inguinal varicocelectomy seem to have comparable effectiveness for adolescents and infertile men with varicoceles. However, the subinguinal approach may have some advantages to deal with painful varicocele. The superior outcomes of bilateral varicocelectomy for patients with clinical left varicocele and concomitant clinical right varicocele are justified, while the benefit is still uncertain for concomitant subclinical right varicocele. Varicocelectomy may have the potential to improve sexual function along with serum testosterone. In conclusion, indications for microsurgical varicocelectomy may be extended by the concomitant right and left clinical varicocele and sexual dysfunction with varicocele.
Sequence conservation of apolipoprotein A-I affords novel insights into HDL structure-function

We performed alignment of apolipoprotein A-I (apoA-I) sequences from 31 species of animals. We found there is specific conservation of salt bridge-forming residues in the first 30 residues of apoA-I and general conservation of a variety of residue types in the central domain, helix 2/3 to helix 7/8. In the lipid-associating domain, helix 7 and helix 10 are the most and least conserved helixes, respectively. Furthermore, eight residues are completely conserved: P66, R83, P121, E191, and P220, and three of seven Tyr residues in human apoA-I, Y18, Y115, and Y192, are conserved. Residue Y18 appears to be important for assembly of HDL. E191-Y192 represents the only completely conserved pair of adjacent residues in apoA-I; Y192 is a preferred target for site-specific oxidative modification within atheroma, and molecular dynamic simulations suggest that the conserved pair E191-Y192 is in a solvent-exposed loop-helix-loop. Molecular dynamics testing of human apoA-I showed that M112 and M148 interact with Y115, a microenvironment unique to human apoA-I. Finally, conservation of Arg residues in the α11/3 helical wheel position 7 supports several possibilities: interactions with adjacent phospholipid molecules and/or oxidized lipids and/or binding of antioxidant enzymes through cation-π orbital interactions. We conclude that sequence alignment of apoA-I provides unique insights into apoA-I structure-function relationship.
Omega-3 fatty acid supplementation and cardiovascular disease

Epidemiological studies on Greenland Inuits in the 1970s and subsequent human studies have established an inverse relationship between the ingestion of omega-3 fatty acids [C20–22 ω 3 polyunsaturated fatty acids (PUFA)], blood levels of C20–22 ω 3 PUFA, and mortality associated with cardiovascular disease (CVD). C20–22 ω 3 PUFA have pleiotropic effects on cell function and regulate multiple pathways controlling blood lipids, inflammatory factors, and cellular events in cardiomyocytes and vascular endothelial cells. The hypolipemic, anti-inflammatory, anti-arrhythmic properties of these fatty acids confer cardioprotection. Accordingly, national heart associations and government agencies have recommended increased consumption of fatty fish or ω 3 PUFA supplements to prevent CVD. In addition to fatty fish, sources of ω 3 PUFA are available from plants, algae, and yeast. A key question examined in this review is whether nonfish sources of ω 3 PUFA are as effective as fatty fish-derived C20–22 ω 3 PUFA at managing risk factors linked to CVD. We focused on ω 3 PUFA metabolism and the capacity of ω 3 PUFA supplements to regulate key cellular events linked to CVD. The outcome of our analysis reveals that nonfish sources of ω 3 PUFA vary in their capacity to regulate blood levels of C20–22 ω 3 PUFA and CVD risk factors.
ENDOSCOPIC NASOBILIARY GALLBLADDER DRAINAGE AFTER ENDOSCOPIC SPHINCTEROTOMY IN PATIENTS WITH ACUTE CHOLECYSTITIS AND CHOLEDOCHOLITHIASIS

A 77‐year‐old man was admitted for the treatment of obstructive jaundice and right hypochondralgia with high fever. An abdominal computed tomography revealed common bile duct stones and acute cholecystitis with gallstones. Magnetic resonance cholangiopancreatography revealed stones in the common bile duct. Endoscopic retrograde cholangiopancreatography also revealed stones in the common bile duct, and immediately endoscopic sphincterotomy was performed. After lithotripsy of the bile duct, continuous endoscopic nasogallbladder drainage was performed successfully. There was severe pus in the gallbladder. Next day, the patient was doing well; there was no pain and fever was down.
Improved methodologies for the study of adipose biology: insights gained and opportunities ahead

Adipocyte differentiation and function have become areas of intense focus in the field of energy metabolism; however, understanding the role of specific genes in the establishment and maintenance of fat cell function can be challenging and complex. In this review, we offer practical guidelines for the study of adipocyte development and function. We discuss improved cellular and genetic systems for the study of adipose biology and highlight recent insights gained from these new approaches.
Carnosine prevents testicular oxidative stress and advanced glycation end product formation in D‐galactose‐induced aged rats

D‐Galactose is shown to mimic natural ageing in rodents by exacerbating oxidative stress and glycation. Steroid production and having a poor antioxidant system make testis vulnerable to galactose‐induced ageing. Antioxidation and antiglycating actions of carnosine may be intriguing for prevention of testicular ageing. In this study, male Wistar rats were applied D‐galactose (300 mg/kg; subcutaneously 5 days a week) and carnosine (250 mg/kg; intraperitoneally 5 days a week) along with D‐galactose for 2 months. D‐Galactose treatment increased testicular reactive oxygen species, thiobarbituric acid reactive substances, diene conjugates, protein carbonyls, advanced oxidation products of proteins and advanced glycation end products. Carnosine was capable of repelling oxidative stress and glycation produced by D‐galactose. Johnsen's score, which describes histopathological evaluation, was also significantly improved with preserved spermatogenesis by carnosine. It appears that carnosine deters the testicular oxidative stress due to galactose‐induced ageing directly by its antioxidative and antiglycating properties.