Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation.

There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.

A novel combination of mutations leading to congenital ichthyosis and ichthyosis vulgaris.

Coexistence of TGM1 and FLG mutations in a newborn with congenital ichthyosis is not well described in the literature. Early genetic testing and counseling are crucial for accurate diagnosis and appropriate management. Further exploration of associated problems, including hearing loss and developmental delay, is warranted in patients with these mutations.

Effects of Transcendental Meditation on Academic Physician Burnout and Depression: A Mixed Methods Randomized Controlled Trial.

INTRODUCTION: Burnout is pervasive among physicians and has widespread implications for individuals and institutions. This research study examines, for the first time, the effects of the Transcendental Meditation (TM) technique on academic physician burnout and depression. METHODS: A mixed methods randomized controlled trial was conducted with 40 academic physicians representing 15 specialties at a medical school and affiliated VA hospital using the TM technique as the active intervention. Physicians were measured at baseline, 1 month, and 4 months using the Maslach Burnout Inventory, Beck Depression Inventory, Insomnia Severity Index, Perceived Stress Scale, and Brief Resilience Scale. Repeated measures analysis of covariance was used to assess adjusted mean change scores for the 1- and 4-months posttests. Qualitative interviews were conducted at baseline and 4 months and compared with the quantitative measurements. RESULTS: Significant improvements were found for the TM group compared with controls at 4 months in total burnout ( p = .020) including the Maslach Burnout Inventory dimensions of emotional exhaustion ( p = .042) and personal accomplishment ( p = .018) and depression ( p = .016). Qualitative interviews supported quantitative outcomes. Physicians reported classic burnout and depression symptoms in baseline interviews. Those regularly practicing the TM technique reported relief from those symptoms. The control group did not state similar changes. DISCUSSION: Mixed methods findings suggest the TM technique is a viable and effective intervention to decrease burnout and depression for academic physicians. Larger longitudinal studies with a wider range of health care providers are needed to validate these findings for extrapolation to the greater medical community.

Echogenic Bowel as an Indicator of Necrotizing Enterocolitis in a Term Newborn.

A 3.5-kilogram infant was born at 40 weeks gestation with an uncomplicated delivery. Prenatal ultrasounds showed echogenic bowel and a ventricular septal defect (VSD), of no clinical significance. Abdominal radiographs showed pneumatosis at 21, 36, and 48 hours of life (HOL). She was treated for necrotizing enterocolitis (NEC) with intravenous antibiotics and parenteral nutrition for 7 days, before working up on feeds and discharging home with breast milk. The only prenatal finding in this case was hyperechogenic bowel, which is a soft marker and often disregarded in the absence of other signs. Chronic intrauterine gut ischemia can cause hyperechogenicity of the bowel. That same intrauterine gut ischemia may have been responsible for NEC in our patient. If a patient has persistent echogenic bowel on prenatal imaging, a critical need exists to make sure NEC is not present.

A Case of Consanguinity.

A newborn of unknown gestational age and unknown chronological age was admitted to the neonatal intensive care unit after presenting to the emergency department for evaluation and concern for neglect. The infant was found at home by authorities with no adult caretaker. As part of routine newborn care, this infant was noted to have an abnormal newborn metabolic screen. Subsequent genetic testing confirmed an inborn error of metabolism. When family and social history became available, it was determined that the mother and putative father were genetically related. This case report discusses newborn metabolic screening and inborn errors of metabolism and their relationship to consanguinity.

A Unique Presentation of Amniotic Band Syndrome: A Newborn With a Tail.

A 1-day-old late preterm, small-for-gestational-age female presented with a caudal appendage-a rare finding-and abnormalities in all 4 limbs most consistent with amniotic band syndrome. The caudal appendage was lateral to midline, measured 3 cm × 0.5 cm, and had no bony abnormalities or spinal cord tethering. Limb abnormalities consisted of brachydactyly, oligodactyly, and syndactyly. Renal and head ultrasounds and an echocardiogram were normal. Chromosomal microarray showed deletion of EPHA3, which is not associated with a known phenotype. The multidisciplinary approach of managing this infant with the rare finding of a caudal appendage and limb abnormalities is presented.

A Stereocontrolled Total Synthesis of Lipoxin B4 and its Biological Activity as a Pro-Resolving Lipid Mediator of Neuroinflammation.

Two stereocontrolled, efficient, and modular syntheses of eicosanoid lipoxin B4 (LXB4 ) are reported. One features a stereoselective reduction followed by an asymmetric epoxidation sequence to set the vicinal diol stereocentres. The dienyne was installed via a one-pot Wittig olefination and base-mediated epoxide ring opening cascade. The other approach installed the diol through an asymmetric dihydroxylation reaction followed by a Horner-Wadsworth-Emmons olefination to afford the common dienyne intermediate. Finally, a Sonogashira coupling and an alkyne hydrosilylation/proto-desilylation protocol furnished LXB4 in 25 % overall yield in just 10 steps. For the first time, LXB4 has been fully characterized spectroscopically with its structure confirmed as previously reported. We have demonstrated that the synthesized LXB4 showed similar biological activity to commercial sources in a cellular neuroprotection model. This synthetic route can be employed to synthesize large quantities of LXB4 , enable synthesis of new analogs, and chemical probes for receptor and pathway characterization.

The NLRP3 Inflammasome in the Pathogenesis and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia. Although AD is one of the most socioeconomically devastating diseases confronting humanity, no "curative" disease modifying drug has been identified. Recent decades have witnessed repeated failures of drug trials and have called into question the utility of the amyloid hypothesis approach to AD therapeutics design. Accordingly, new neurochemical processes are being evaluated and explored as sources of alternative druggable targets. Among these newly identified targets, neuroinflammation is emerging as a front-runner, and within the realm of neuroinflammation, the inflammasome, particularly the NLRP3 complex, is garnering focussed attention. This review summarizes current data and approaches to understanding the role of the NLRP3 inflammasome in neuroinflammation and AD, and systematically identifies and evaluates multiple targets within the NLRP3 inflammasome cascade as putative drug targets.

Teacher and Student Views on the Feasibility of Peer to Peer Education as a Model to Educate 16-18 Year Olds on Prudent Antibiotic Use-A Qualitative Study.

Peer education (PE) has been used successfully to improve young peoples' health-related behaviour. This paper describes a qualitative evaluation of the feasibility of university healthcare students delivering PE, covering self-care and antibiotic use for infections, to biology students in three UK schools (16-18 years), who then educated their peers. Twenty peer educators (PEds) participated in focus groups and two teachers took part in interviews to discuss PE feasibility. Data were analysed inductively. All participants reported that teaching students about antibiotic resistance was important. PE was used by PEds to gain communication skills and experience for their CV. PEds confidence increased with practice and group delivery. Interactive activities and real-life illness scenarios facilitated enjoyment. Barriers to PE were competing school priorities, no antibiotic content in the non-biology curriculum, controlling disruptive behaviour, and evaluation consent and questionnaire completion. Participation increased PEds' awareness of appropriate antibiotic use. This qualitative study supports the feasibility of delivering PE in schools. Maximising interactive and illness scenario content, greater training and support for PEds, and inclusion of infection self-care and antibiotics in the national curriculum for all 16-18-year olds could help facilitate greater antibiotic education in schools. Simplifying consent and data collection procedures would facilitate future evaluations.

Peer-Education as a Tool to Educate on Antibiotics, Resistance and Use in 16-18-Year-Olds: A Feasibility Study.

Peer education (PE) interventions may help improve knowledge and appropriate use of antibiotics in young adults. In this feasibility study, health-care students were trained to educate 16-18 years old biology students, who then educated their non-biology peers, using e-Bug antibiotic lessons. Knowledge was assessed by questionnaires, and antibiotic use by questionnaire, SMS messaging and GP record searches. Five of 17 schools approached participated (3 PE and 2 control (usual lessons)). 59% (10/17) of university students and 28% (15/54) of biology students volunteered as peer-educators. PE was well-received; 30% (38/127) intervention students and 55% (66/120) control students completed all questionnaires. Antibiotic use from GP medical records (54/136, 40% of students' data available), student SMS (69/136, 51% replied) and questionnaire (109/136, 80% completed) data showed good agreement between GP and SMS (kappa = 0.72), but poor agreement between GP and questionnaires (kappa = 0.06). Median knowledge scores were higher post-intervention, with greater improvement for non-biology students. Delivering and evaluating e-Bug PE is feasible with supportive school staff. Single tiered PE by university students may be easier to regulate and manage due to time constraints on school students. SMS collection of antibiotic data is easier and has similar accuracy to GP data.

International promotion of e-Bug, an infection prevention and control educational intervention: survey of partners across 14 countries.

BACKGROUND: Antimicrobial resistance (AMR) is a global threat to public health. e-Bug is an educational resource developed and promoted by a network of international partners. e-Bug seeks to reduce the spread of infection and use of antimicrobials in young people and the community, so helping to control AMR. This study aimed to explore how e-Bug is promoted by international partners and observe barriers to promotion, including the extent of education about antibiotics in schools. METHODS: A total of 29 e-Bug partners were invited to complete online questionnaires on (i) methods they use to promote e-Bug; and (ii) antibiotic topics covered in the national curriculum in their countries. RESULTS: Fourteen and 15 of 29 e-Bug partners across Europe and Palestine completed the promotional activities and curriculum questionnaires respectively. The most frequently reported methods of promotion included endorsement and collaboration with government and non-government sectors and involvement in national and global health awareness campaigns. Barriers to promotion included a lack of time and funding. The curriculum survey data showed variation in antibiotic education across Europe and Palestine, lack of antibiotic education for children under 11 years of age and little change in antibiotic topics included in the curriculum since 2006. CONCLUSIONS: Future and existing e-Bug partners should be encouraged to follow promotional activities reported in this paper, including ministry endorsement, educator training, international campaigns and youth programmes. We encourage all countries to increase antibiotic topics in the school curriculum across all ages.

Asymmetric Entry into 10b-aza-Analogues of Amaryllidaceae Alkaloids Reveals a Pronounced Electronic Effect on Antiviral Activity.

Development of a chiral pool-based synthesis of 10b-aza-analogues of biologically active Amaryllidaceae alkaloids is described, involving a concise reductive amination and condensation sequence, leading to ring-B/C-modified, fully functionalized ring-C derivatives. Differentiated anticancer and antiviral activities of these analogues are presented. Despite complete conformational and functional group overlap, the 10b-aza-analogues have diminished anticancer activity and no antiviral activity. These unprecedented electronic effects suggest a possible role for π-type secondary orbital interactions with the biological target.

Current climate for digital game-based learning of science in further and higher education.

Digital game-based learning (DGBL) is being used increasingly as an alternative learning tool to teach science in further and higher education. A variety of digital game formats currently exist for science learning, alongside diverse methods for their implementation and evaluation. This paper aims to provide a broad summary of the field by discussing the current platforms for DGBL and examples of games played on them. These include gamified simulations and traditional digital games delivered through personal computer and online software; mobile games delivered through downloaded applications for devices such as tablets and mobile phones; and educational modifications of commercial games, known amongst gamers as 'mods'. To conclude the summary, the paper discusses the current challenges and barriers associated with DGBL in further and higher science education, and potential strategies researchers may consider to overcome them.

One-pot, multicomponent synthesis of 2,3-disubstituted quinazolin-ones with potent and selective activity against Toxoplasma gondii.

The discovery of two quinazolinones with selective, single-digit micromolar activity (IC50 = 6-7 µM) against the tachyzoites of the apicomplexan parasite Toxoplasma gondii is reported. These potent and selective third generation derivatives contain a benzyloxybenzyl substituent at C2 and a bulky aliphatic moiety at N3. Here we show that these quinazolinones inhibit T. gondii tachyzoite replication in an established infection, but do not significantly affect host cell invasion by the tachyzoites.

Three new polyketides from fruiting bodies of the endophytic ascomycete Xylaria polymorpha.

The isolation of three new secondary metabolites from the fruiting body of Xylaria polymorpha is described. The new compounds are of mixed biosynthetic origin consisting of a polyketide starter, extended with a methyl orsellinate unit and terminated hydrolytically or with an amine-containing terminal unit.

Discovery of potent antiviral (HSV-1) quinazolinones and initial structure-activity relationship studies.

The discovery of antiviral activity of 2,3-disubstituted quinazolinones, prepared by a one-pot, three-component condensation of isatoic anhydride with amines and aldehydes, against Herpes Simplex Virus (HSV)-1 is reported. Sequential iterative synthesis/antiviral assessment allowed structure-activity relationship (SAR) generation revealing synergistic structural features required for potent anti-HSV-1 activity. The most potent derivatives show greater efficacy than acyclovir against acute HSV-1 infections in neurons and minimal toxicity to the host.

Comparison of three cell-based drug screening platforms for HSV-1 infection.

Acyclovir (ACV) and its derivatives have been highly effective for treating recurrent, lytic infections with Herpes Simplex Virus, type 1 (HSV-1), but searches for additional antiviral drugs are motivated by recent reports of resistance to ACV, particularly among immunocompromised patients. In addition, the relative neurotoxicity of ACV and its inability to prevent neurological sequelae among HSV-1 encephalitis survivors compel searches for new drugs to treat HSV-1 infections of the central nervous system (CNS). Primary drug screens for neurotropic viruses like HSV-1 typically utilize non-neuronal cell lines, but they may miss drugs that have neuron specific antiviral effects. Therefore, we compared the effects of a panel of conventional and novel anti-herpetic compounds in monkey epithelial (Vero) cells, human induced pluripotent stem cells (hiPSCs)-derived neural progenitor cells (NPCs) and hiPSC-derived neurons (N = 73 drugs). While the profiles of activity for the majority of the drugs were similar in all three tissues, Vero cells were less likely than NPCs to identify drugs with substantial inhibitory activity in hiPSC-derived neurons. We discuss the relative merits of each cell type for antiviral drug screens against neuronal infections with HSV-1.

Enol ethers as carbonyl surrogates in a modification of the Povarov synthesis of 3-aryl quinolines and their anti-Toxoplasma activity.

A novel method for the preparation of 2-carboxyl-3-aryl quinoline derivatives from anilines, ethyl glyoxalate and enol ethers as phenylacetaldehyde surrogates is reported. The three-component coupling reaction occurs rapidly under mild conditions in dichloromethane catalysed by TFA. The method allows a more direct access to 3-aryl quinolines, sidestepping issues encountered with phenylacetaldehyde derivatives. This chemistry was used to prepare quinolines with 3-diarylether functionality that showed low micromolar efficacy (IC50 range: 5-26 µM) against in vitro Toxoplasma gondii coupled with little or no cytotoxicity (TD50≥ 320 µM) towards the host cells.

Activity of Species-specific Antibiotics Against Crohn's Disease-Associated Adherent-invasive Escherichia coli.

BACKGROUND: Crohn's disease (CD) is associated with bacterial dysbiosis that frequently includes colonization by adherent-invasive Escherichia coli (AIEC). AIEC are adept at forming biofilms and are able to invade host cells and stimulate the production of proinflammatory cytokines. The use of traditional antibiotics for the treatment of CD shows limited efficacy. In this study, we investigate the use of species-specific antibiotics termed colicins for treatment of CD-associated AIEC. METHODS: Colicin activity was tested against a range of AIEC isolates growing in the planktonic and biofilm mode of growth. Colicins were also tested against AIEC bacteria associated with T84 intestinal epithelial cells and surviving inside RAW264.7 macrophages using adhesion assays and gentamicin protection assay, respectively. Uptake of colicins into eukaryotic cells was visualized using confocal microscopy. The effect of colicin treatment on the production of proinflammatory cytokine tumor necrosis factor alpha by macrophages was assessed by an enzyme-linked immunosorbent assay. RESULTS: Colicins show potent activity against AIEC bacteria growing as biofilms when delivered either as a purified protein or through a colicin-producing bacterial strain. In addition, colicins E1 and E9 are able to kill cell-associated and intracellular AIEC, but do not show toxicity toward macrophage cells or stimulate the production of proinflammatory cytokines. Colicin killing of intracellular bacteria occurs after entry of colicin protein into AIEC-infected macrophage compartments by actin-mediated endocytosis. CONCLUSIONS: Our results demonstrate the potential of colicins as highly selective probiotic therapeutics for the eradication of E. coli from the gastrointestinal tract of patients with CD.