Tuning Molecular Motion Enhances Intrinsic Fluorescence in Peptide Amphiphile Nanofibers.

Peptide amphiphiles (PAs) are highly tunable molecules that were recently found to exhibit aggregation-induced emission (AIE) when they self-assemble into nanofibers. Here, we leverage decades of molecular design and self-assembly study of PAs to strategically tune their molecular motion within nanofibers to enhance AIE, making them a highly useful platform for applications such as sensing, bioimaging, or materials property characterization. Since AIE increases when aggregated molecules are rigidly and closely packed, we altered the four most closely packed amino acids nearest to the hydrophobic core by varying the order and composition of glycine, alanine, and valine pairs. Of the six PA designs studied, C16VVAAK2 had the highest quantum yield at 0.17, which is a more than 10-fold increase from other PA designs including the very similar C16AAVVK2, highlighting the importance of precise amino acid placement to anchor rigidity closest to the core. We also altered temperature to increase AIE. C16VVAAK2 exhibited an additional 4-fold increase in maximum fluorescence intensity when the temperature was raised from 5 to 65 °C. As the temperature increased, the secondary structure transitioned from ß-sheet to random coil, indicating that further packing an already aligned molecular system makes it even more readily able to transfer energy between the electron-rich amides. This work both unveils a highly fluorescent AIE PA system design and sheds insights into the molecular orientation and packing design traits that can significantly enhance AIE in self-assembling systems.

Non-Heme Iron Enzymes Catalyze Heterobicyclic and Spirocyclic Isoquinolone Core Formation in Piperazine Alkaloid Biosynthesis.

We report the discovery and biosynthesis of new piperazine alkaloids-arizonamides, and their derived compounds-arizolidines, featuring heterobicyclic and spirocyclic isoquinolone skeletons, respectively. Their biosynthetic pathway involves two crucial non-heme iron enzymes, ParF and ParG, for core skeleton construction. ParF has a dual function facilitating 2,3-alkene formation of helvamide, as a substrate for ParG, and oxidative cleavage of piperazine. Notably, ParG exhibits catalytic versatility in multiple oxidative reactions, including cyclization and ring reconstruction. A key amino acid residue Phe67 was characterized to control the formation of the constrained arizonamide B backbone by ParG.

Gustavson syndrome is caused by an in-frame deletion in RBMX associated with potentially disturbed SH3 domain interactions.

RNA binding motif protein X-linked (RBMX) encodes the heterogeneous nuclear ribonucleoprotein G (hnRNP G) that regulates splicing, sister chromatid cohesion and genome stability. RBMX knock down experiments in various model organisms highlight the gene's importance for brain development. Deletion of the RGG/RG motif in hnRNP G has previously been associated with Shashi syndrome, however involvement of other hnRNP G domains in intellectual disability remain unknown. In the current study, we present the underlying genetic and molecular cause of Gustavson syndrome. Gustavson syndrome was first reported in 1993 in a large Swedish five-generation family presented with profound X-linked intellectual disability and an early death. Extensive genomic analyses of the family revealed hemizygosity for a novel in-frame deletion in RBMX in affected individuals (NM_002139.4; c.484_486del, p.(Pro162del)). Carrier females were asymptomatic and presented with skewed X-chromosome inactivation, indicating silencing of the pathogenic allele. Affected individuals presented minor phenotypic overlap with Shashi syndrome, indicating a different disease-causing mechanism. Investigation of the variant effect in a neuronal cell line (SH-SY5Y) revealed differentially expressed genes enriched for transcription factors involved in RNA polymerase II transcription. Prediction tools and a fluorescence polarization assay imply a novel SH3-binding motif of hnRNP G, and potentially a reduced affinity to SH3 domains caused by the deletion. In conclusion, we present a novel in-frame deletion in RBMX segregating with Gustavson syndrome, leading to disturbed RNA polymerase II transcription, and potentially reduced SH3 binding. The results indicate that disruption of different protein domains affects the severity of RBMX-associated intellectual disabilities.

Experience With the Routine Use of Electronic Patient-Reported Outcome Measures for Patients With Lung Cancer.

PURPOSE: The Christie NHS Foundation Trust launched their electronic patient-reported outcome measures (ePROMs) service in January 2019 in the routine clinical setting. The lung cancer questionnaires consist of 14 symptom items, adapted from the Common Terminology Criteria for Adverse Events (version 5.0) and the EuroQol EQ-5D-5L quality-of-life (QoL) tool. Patients with lung cancer are invited to complete questionnaires assessing their symptoms and QoL using an online platform. METHODS: The ePROM responses and clinical, pathologic, and treatment data for patients who completed the questionnaires between January 2019 and December 2020 were extracted from electronic medical records. The symptom and QoL scores of patients who completed baseline pretreatment ePROMs and also those who completed ePROMs pre- and postpalliative lung systemic anticancer therapy (SACT) or radical thoracic radiotherapy were evaluated. Pretreatment questionnaires were analyzed according to age, Eastern Cooperative Oncology Group performance status (ECOG PS), and Adult Comorbidity Evaluation-27 (ACE-27) comorbidity score. RESULTS: One thousand four hundred eighty patients with lung cancer were included. There were no statistically significant differences in symptoms and QoL scores between age groups. Cough (P = .006) and EQ-5D-5L mobility scores (P = .006) were significantly worse for patients with an ECOG PS of 0-1. Dyspnea (P = .035), hemoptysis (P = .023), nausea (P = .041), mobility (P = .004), and self-care (P = .0420) were significantly worse for those with higher ACE-27 scores (2-3 v 0-1). Palliative SACT was associated with a significant improvement in cough (P < .001) and hemoptysis (P = .025), but significantly negatively affected mobility (P = .013). Patients receiving radical thoracic radiotherapy reported a significant improvement in hemoptysis (P = .042) but worse pain (P = .002) and fatigue (P = .01). Other changes in symptom and QoL scores were not significant. CONCLUSION: The symptoms and QoL reported at baseline and before and after both palliative SACT and radical thoracic radiotherapy are clinically relevant and meaningful. We have demonstrated that routine implementation of ePROMs into clinical practice is feasible and can inform clinical practice and future research.

Highly sensitive detection of EGFR L858R mutation at the mRNA level.

The missense mutation EGFR L858R implies increased sensitivity to EGFR tyrosine kinase inhibitor (TKIs) therapy, despite a significant non-response rate. Currently, detection of EGFR L858R mutation is mostly DNA based, therefore, the allele-specific expression level of the mutated gene and its clinical relevance is hidden. Based on the extendable blocking probes and hot-start protocol for reverse transcription, we have developed and validated a novel one-step realtime RT-PCR assay that enables detection of EGFR L858R mutation at the mRNA level. This RNA-based assay was able to detect the EGFR L858R mutation in a 10,000-fold excess of its wildtype counterpart, indicating an analytical sensitivity of 0.01%. In comparison to the reference DNA-based assay, the RNA-based assay further detected the EGFR L858R mutation in significantly additional formalin-fixed paraffin-embedded (FFPE) samples (19.2% vs 15.0%). Interestingly, our data showed that the relative mRNA levels of EGFR L858R mutation varied greatly in tumor tissues (∼4 logs); and the circulating mRNA of EGFR L858R mutation was detectable in plasma of NSCLC patients. This novel RNA-based PCR assay provides a simple and ultrasensitive tool for detection of EGFR L858R mutation at the mRNA level as a new class of biomarkers.

Characterization of PCDD/Fs and dioxin-like PCBs in flue gas from thermal industrial processes in Vietnam: A comprehensive investigation on emission profiles and levels.

The emission profiles and levels of unintentionally produced persistent organic pollutants (U-POPs) comprising polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (dl-PCBs) were comprehensively investigated in flue gas released from 20 facilities belonging to 11 thermal industrial processes in Vietnam. Levels and patterns of PCDD/Fs and dl-PCBs in flue gas samples varied widely between sectors and different facilities in the same sector, suggesting different formation mechanisms involved. Flue gas concentrations of PCDD/Fs and dl-PCBs generally decreased in the order: industrial waste incinerator > secondary zinc production > coal fired craft boiler > coal fired power plant ≈ medical waste incinerator > steel production ≈ cement production > secondary copper production > coal fired industrial boiler > secondary tin production ≈ municipal waste incinerator. Results obtained from diagnostic ratio and fingerprint analysis have revealed that the stack emissions of PCDD/Fs and dl-PCBs were probably attributed to the de novo formation and incomplete destruction of input materials containing technical PCB oils or paints. The average emission factors of PCDD/Fs and dl-PCBs ranged from 0.011 to 374 µg WHO-TEQ tonne-1 for the studied facilities. A total emission amount of 4.89-11.4 g WHO-TEQ year-1 was estimated for the 20 facilities investigated in our study. This is the first comprehensive investigation on the unintentional emissions of PCDD/Fs and dl-PCBs from a wide range of industrial sectors in Vietnam.

A systematic review and meta-analysis of the effectiveness of food safety education interventions for consumers in developed countries.

BACKGROUND: Foodborne illness has a large public health and economic burden worldwide, and many cases are associated with food handled and prepared at home. Educational interventions are necessary to improve consumer food safety practices and reduce the associated burden of foodborne illness. METHODS: We conducted a systematic review and targeted meta-analyses to investigate the effectiveness of food safety education interventions for consumers. Relevant articles were identified through a preliminary scoping review that included: a comprehensive search in 10 bibliographic databases with verification; relevance screening of abstracts; and extraction of article characteristics. Experimental studies conducted in developed countries were prioritized for risk-of-bias assessment and data extraction. Meta-analysis was conducted on data subgroups stratified by key study design-intervention-population-outcome categories and subgroups were assessed for their quality of evidence. Meta-regression was conducted where appropriate to identify possible sources of between-trial heterogeneity. RESULTS: We identified 79 relevant studies: 17 randomized controlled trials (RCTs); 12 non-randomized controlled trials (NRTs); and 50 uncontrolled before-and-after studies. Several studies did not provide sufficient details on key design features (e.g. blinding), with some high risk-of-bias ratings due to incomplete outcome data and selective reporting. We identified a moderate to high confidence in results from two large RCTs investigating community- and school-based educational training interventions on behaviour outcomes in children and youth (median standardized mean difference [SMD] = 0.20, range: 0.05, 0.35); in two small RCTs evaluating video and written instructional messaging on behavioural intentions in adults (SMD = 0.36, 95% confidence interval [CI]: 0.02, 0.69); and in two NRT studies for university-based education on attitudes of students and staff (SMD = 0.26, 95% CI: 0.10, 0.43). Uncontrolled before-and-after study outcomes were very heterogeneous and we have little confidence that the meta-analysis results reflect the true effect. Some variation in outcomes was explained in meta-regression models, including a dose effect for behaviour outcomes in RCTs. CONCLUSIONS: In controlled trials, food safety education interventions showed significant effects in some contexts; however, many outcomes were very heterogeneous and do not provide a strong quality of evidence to support decision-making. Future research in this area is needed using more robust experimental designs to build on interventions shown to be effective in uncontrolled before-and-after studies.

Scoping Review of Research on the Effectiveness of Food-Safety Education Interventions Directed at Consumers.

Improper food handling by consumers at home is a major cause of foodborne illness. Therefore, effective education strategies are essential to change consumers' food safety attitudes and behaviors. The purpose of this scoping review was to identify and characterize primary literature examining the effectiveness of consumer food-safety education interventions. Ten bibliographic databases were searched using a comprehensive search strategy. Citations were identified; two reviewers screened them for relevance and characterized relevant articles. To ensure results would be applicable to end users, stakeholders were engaged to provide input on the review scope, methods, and results. We identified 246 relevant articles, of which 150 were quantitative, 66 qualitative, and 30 mixed-method research studies. Most studies (64.2%) were published in the United States, using an uncontrolled before-and-after study design (31.3%), and investigated the effectiveness of community-based training sessions and workshops (52.0%). Research gaps were found in the number of randomized controlled studies conducted, academic- and school-based courses and curricula investigated, and interventions targeting high-risk populations (e.g., pregnant women, those who are immunocompromised) and using new media channels (e.g., social media). Key opportunities to enhance the utility of future primary research investigating consumer food-safety interventions include the following: using studies based on behavior-change theories and formative research; engaging the target population in the research; using validated instruments to measures outcomes; and reporting intervention characteristics and outcomes completely. Results of this review can be used to prioritize future primary research and decision-making in this area.

Nonarteritic ischemic optic neuropathy secondary to severe ocular hypertension masked by interface fluid in a post-LASIK eye.

UNLABELLED: We report a case of ischemic optic neuropathy arising from elevated intraocular pressure (IOP) masked by interface fluid in a post-laser in situ keratomileusis (LASIK) eye. A 51-year-old man, who had had LASIK 6 years prior to presentation, sustained blunt trauma to the left eye that resulted in a hyphema and ocular hypertension. Elevated IOP resulted in accumulation of fluid in the stromal bed-LASIK flap interface, leading to underestimation of IOP when measured centrally over the flap. After days of unrecognized ocular hypertension, ischemic optic neuropathy developed. To our knowledge, this is the first reported case of ischemic optic neuropathy resulting from underestimated IOP measurements in a post-LASIK patient. It highlights the inaccuracy of IOP measurements in post-LASIK eyes and a vision-threatening potential complication. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Conversion of Weinreb amides into benzene rings incorporating the amide carbonyl carbon.

Esters, acids and acid chlorides can be converted via the intermediacy of their corresponding Weinreb amides into benzene derivatives that incorporate the original carbonyl carbon as part of the benzene ring. The process involves treatment of the derived Weinreb amides with 3-butenylmagnesium bromide and an allylic Grignard reagent, followed by ring-closing metathesis, dehydration and dehydrogenation. The dehydration-dehydrogenation can be done under acidic conditions with a mixture of TsOH x H(2)O and DDQ or in two steps with SOCl(2)/pyridine, followed by treatment with DDQ. Application of the method to carbohydrates provides a convenient route to C-5 aryl pyranosides.

Endovascular repair of an iatrogenic superior vena caval injury: a case report.

We present the case of a patient with an iatrogenic injury to the superior vena cava during a central venous catheter placement. The vena cava was perforated when a left subclavian dialysis catheter was placed. The perforation in the right side of the vena cava occurred at the confluence of the innominate veins. This perforation was successfully repaired using a 10 mm Viabahn stent graft (W. L. Gore, Flagstaff, Ariz) delivered through a femoral approach. The stent graft was deployed as the dialysis catheter was removed. This case demonstrates the utility of stent graft repair of the superior vena cava in emergency situations.

Management of distal femoral and popliteal arterial injuries: an update.

BACKGROUND: The management of combined arterial and musculoskeletal injuries to the lower extremity remains controversial, particularly with regard to the initial order of intervention and the use of intravascular shunting. In this study, we review the contemporary management and outcome of patients treated for acute traumatic distal femoropopliteal arterial injuries. METHODS: From January 2001 to January 2006, we repaired 57 acute traumatic lower-extremity arterial injuries in a level 1 trauma center. Our approach was to perform surgical revascularization without intraluminal shunting as soon as the arterial injury was recognized. There were 44 men (77%). Mean age was 31 years (range, 5-68). The mechanism of injury was blunt in 42 of 57 (74%) patients. Vascular reconstruction was achieved by using an autogenous saphenous vein graft in 52 of 57 (91%), a vein patch in 3 of 57 (5%), or primarily in 2 of 57 (4%) patients. RESULTS: The limb-salvage rate was 92% (53/57). Thirty-six patients (63%) had associated orthopedic fixation: 12 of 36 (33%) before and 24 of 36 (67%) after revascularization. Twenty-one of 57 patients (37%) had vascular repair only without orthopedic fixation. Thirty-four patients (60%) required fasciotomy. Four patients had subsequent above-knee amputation: 3 because of wound complications despite successful revascularization and 1 because of failed revascularization. There were no complications related to the arterial repairs that were performed before orthopedic fixation. CONCLUSION: Our study shows that arterial reconstruction for acute traumatic lower-limb injuries results in a good limb-salvage rate. We advocate prompt vascular repair before orthopedic intervention for combined vascular and skeletal injuries of the lower extremity, without using intravascular shunting.