Devimistat (CPI-613) With Modified Fluorouarcil, Oxaliplatin, Irinotecan, and Leucovorin (FFX) Versus FFX for Patients With Metastatic Adenocarcinoma of the Pancreas: The Phase III AVENGER 500 Study.

PURPOSE: Metastatic pancreatic adenocarcinoma (mPC) remains a difficult-to-treat disease. Fluorouarcil, oxaliplatin, irinotecan, and leucovorin (FFX) is a standard first-line therapy for mPC for patients with a favorable performance status and good organ function. In a phase I study, devimistat (CPI-613) in combination with modified FFX (mFFX) was deemed safe and exhibited promising efficacy in mPC. METHODS: The AVENGER 500 trial (ClinicalTrials.gov identifier: NCT03504423) is a global, randomized phase III trial conducted at 74 sites across six countries to investigate the efficacy and safety of devimistat in combination with mFFX (experimental arm) compared with standard-dose FFX (control arm) in treatment-naïve patients with mPC. Treatment, administered in once-every-2-weeks cycles until disease progression or intolerable toxicity, included intravenous devimistat at 500 mg/m2 total per day on days 1 and 3 in the experimental arm. The primary end point of the study was overall survival (OS). RESULTS: Five hundred and twenty-eight patients were randomly assigned (266 in the experimental arm and 262 in the control arm). The median OS was 11.10 months for devimistat plus mFFX versus 11.73 months for FFX (hazard ratio [HR], 0.95 [95% CI, 0.77 to 1.18]; P = .655) and median progression-free survival was 7.8 months versus 8.0 months, respectively (HR, 0.99 [95% CI, 0.76 to 1.29]; P = .94). Grade ≥3 treatment-emergent adverse events with >10% frequency in the devimistat plus mFFX arm versus the FFX arm were neutropenia (29.0% v 34.5%), diarrhea (11.2% v 19.6%), hypokalemia (13.1% v 14.9%), anemia (13.9% v 13.6%), thrombocytopenia (11.6% v 13.6%), and fatigue (10.8% v 11.5%), respectively. CONCLUSION: Devimistat in combination with mFFX did not improve long- and short-term mPC patient outcomes compared with standard FFX. There were no new toxicity signals with the addition of devimistat.

Behavioral and electrophysiological responses of the male medfly, Ceratitis capitata, to thymol and carvacrol ethers.

BACKGROUND: The Mediterranean fruit fly, Ceratitis capitata, is one of the most economically important insect pests attacking fruits and vegetables in tropical and subtropical areas of the world. Semiochemical-based pest management programs are being used to provide environmentally friendly control methods for medflies. The goals of the current study were to discover potential new, attractive, kairomones by designing, synthesizing, and testing simplified ethers of thymol and carvacrol along with their ether derivatives in short-range attraction assays and electroantennogram (EAG) assays with male C. capitata. To the best of our knowledge, this study represents the first investigation of thymol and carvacrol, and their respective ethers for attractancy to C. capitata, a major agricultural pest worldwide. RESULTS: In short-range attraction bioassays, parent compounds, thymol and carvacrol, along with their propyl, butyl, benzyl, and octyl ethers captured the most male C. capitata. The attraction patterns changed over time and captures were only significant if they were greater than the positive control tea tree oil (TTO) at 90 min. In EAG assays, thymol benzyl, octyl ethers, and carvacrol benzyl ether evoked significantly greater antennal responses than their parent compounds. The EAG responses did not correlate with short-range male attraction. The aliphatic side chains of thymol and carvacrol had a small effect on the activity. Future studies will investigate the long-range attraction of the ethers that elicited large EAG responses. CONCLUSION: This report provides new information for discovering potential kairomones through synthesis and structure-activity studies for sterile male medflies. Thymol, carvacrol, and several of their ether derivatives displayed improved longevity of attraction compared with TTO (a strong medfly attractant), with significantly higher captures than TTO observed at 90 min in laboratory bioassays. Further chemical synthesis of thymol and carvacrol ethers within this series may lead to the development of ethers that are more attractive or persistent than their parent compounds, thymol and carvacrol. © 2024 Society of Chemical Industry. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

How to interpret and apply the results of indirect calorimetry studies: a case-based tutorial.

Evidence is growing that the individual adjustment of energy targets guided by indirect calorimetry (IC) can improve outcome. With the development of a new generation of devices that are easier to use and rapid, it appears important to share knowledge and expertise that may be used to individualize nutrition care. Despite the focus of this tutorial being on one contemporary device, the principles of IC apply across existing devices and can assist tailoring the nutrition prescription and in assessing response to nutrition therapy. The present tutorial addresses its clinical application in intubated mechanically ventilated and spontaneously breathing adult patients (canopy), i.e. it covers the range from critical illness to outpatients. The cases that are presented show how the measured energy expenditure (mEE), and the respiratory quotient (RQ), i.e. the ratio of expired CO2 to consumed O2, should be applied in different cases, to adapt and individualize nutrition prescription, as it is a good marker of over- or underfeeding at the different stages of disease. The RQ also informs about the patient's body's capacity to use different substrates: the variations of RQ indicating the metabolic changes revealing insufficient or excessive feeding. The different cases reflect the use of a new generation device as a metabolic monitor that should be combined with other clinical observations and laboratory biomarkers. The tutorial also points to some shortcomings of the method, proposing alternatives.

Parental Report of Indoor Air Pollution is Associated with Respiratory Morbidities In Bronchopulmonary Dysplasia.

OBJECTIVE: To determine the association between indoor air pollution and respiratory morbidities in children with bronchopulmonary dysplasia recruited from the multicenter Bronchopulmonary Dysplasia (BPD) Collaborative. STUDY DESIGN: A cross-sectional study was performed among participants less than 3 years old in the BPD Collaborative Outpatient Registry. Indoor air pollution was defined as any reported exposure to tobacco or marijuana smoke, electronic cigarette emissions, gas stoves, and/or wood stoves. Clinical data included acute care use and chronic respiratory symptoms in the past 4 weeks. RESULTS: A total of 1,011 subjects born at a mean gestational age of 26.4 ± 2.2 weeks were included. Most (66.6%) had severe BPD. Over 40% of subjects were exposed to at least one source of indoor air pollution. The odds of reporting an emergency department visit (OR 1.7 [1.18, 2.45], antibiotic use (OR 1.9 [1.12, 3.21]), or a systemic steroid course (OR 2.18 [1.24, 3.84]) were significantly higher in subjects reporting exposure to secondhand smoke (SHS) compared with those without SHS exposure. Subjects reporting exposure to air pollution (not including SHS) also had a significantly greater odds (OR 1.48 [1.08, 2.03]) of antibiotic use as well. Indoor air pollution exposure (including SHS) was not associated with chronic respiratory symptoms or rescue medication use. CONCLUSION: Exposure to indoor air pollution, especially SHS, was associated with acute respiratory morbidities, including ED visits, antibiotics for respiratory illnesses, and systemic steroid use.

Luminescence-based complementation assay to assess target engagement and cell permeability of glycolate oxidase (HAO1) inhibitors.

Glycolate oxidase (HAO1) catalyses the synthesis of glyoxylate, a common metabolic intermediate that causes renal failure if accumulated. HAO1 inhibition is an emerging treatment for primary hyperoxaluria, a rare disorder of glyoxylate metabolism. Here we report the first cell-based measurement of inhibitor uptake and engagement with HAO1, by adapting the cellular thermal shift assay (CETSA) based on Nano luciferase complementation and luminescence readout. By profiling the interaction between HAO1 and four well-characterised inhibitors in intact and lysed HEK293T cells, we showed that our CETSA method differentiates between low-permeability/high-engagement and high-permeability/low-engagement ligands and is able to rank HAO1 inhibitors in line with both recombinant protein methods and previously reported indirect cellular assays. Our methodology addresses the unmet need for a robust, sensitive, and scalable cellular assay to guide HAO1 inhibitor development and, in broader terms, can be rapidly adapted for other targets to simultaneously monitor compound affinity and cellular permeability.

Development and content validation of a questionnaire identifying patients' functional priorities and abilities after hip or knee arthroplasty.

PURPOSE: To develop a self-report questionnaire evaluating functional priorities after hip or knee arthroplasty and evaluate patients' understanding of its items and conceptual relevance. METHODS: A self-report questionnaire was first developed based on the International Classification of Functioning, Disability, and Health (ICF) core set for osteoarthritis (OA). In the second stage, two research physiotherapists thoroughly reviewed and refined the questionnaire, and another physiotherapist conducted cognitive think-aloud interviews with 18 patients to assess the face and content validity of the questionnaire. RESULTS: All categories and corresponding activities of ICF core set for OA were used to develop the questionnaire. Several questionnaire issues were identified and addressed. Most challenges were related to comprehension, followed by item ordering and visual elements. Patients identified ambiguous wording which we subsequently simplified. Ten activities of the core set were excluded due to lack of face validity, two activities were added, and four activities were modified. CONCLUSION: The findings suggest that the ICF core set for OA needs to be adjusted for patients undergoing hip or knee arthroplasty and highlight the feasibility of applying a modified core set to assess functional priorities after hip or knee arthroplasty.

The questionnaire developed in this study can be used to assess patients' functional priorities after hip or knee arthroplasty for osteoarthritis.Several activities that comprise the International Classification of Functioning, Disability and Health (ICF) core set for osteoarthritis could be used to assess functional priorities after hip or knee arthroplasty.Some categories need to be removed or modified within this core set based on feedback from patients during the think-aloud sessions in our study.Using our questionnaire to determine postoperative patient priorities can help identify appropriate patient-centered outcome measures to use after hip or knee arthroplasty.

Left-right tympanal size asymmetry in the parasitoid fly Ormia ochracea.

Ormia ochracea is a parasitoid fly notable for its impressive hearing abilities relative to its small size. Here, we use it as a model organism to investigate if minor size differences in paired sensory organs may be beneficial or neutral to an organism's perception abilities. We took high-resolution images of tympanal organs from 21 O. ochracea specimens and found a statistically significant surface area asymmetry (up to 6.88%) between the left and right membranes. Numerical experiments indicated that peak values of key sound localization variables increased with increasing tympanal asymmetry, which may explain features of the limited available physiological data.

Characterizing dispersion in bovine liver using ARFI-based shear wave rheometry.

Background: Dispersion presents both a challenge and a diagnostic opportunity in shear wave elastography (SWE). Shear Wave Rheometry (SWR) is an inversion technique for processing SWE data acquired using an acoustic radiation force impulse (ARFI) excitation. The main advantage of SWR is that it can characterize the shear properties of homogeneous soft media over a wide frequency range. SWR was used here to measure the shear properties of bovine liver tissue. Assumptions associated with SWR include tissue homogeneity, tissue isotropy, and axisymmetry of the ARFI excitation. Objective: Evaluate the validity of the SWR assumptions in ex vivo bovine liver. Approach: SWR was used to measure the shear properties of bovine liver tissue as a function of frequency, over a large frequency range. Assumptions associated with SWR (homogeneity, isotropy and axisymmetry) were evaluated through measurements performed at multiple locations and probe orientations. Main results: Measurements of shear properties were obtained over the 25-250 Hz range, and showed a 4-fold increase in shear storage modulus (from 1 to 4 kPa) and over a 10-fold increase in the loss modulus (from 0.2 to 3 kPa) over that decade-wide frequency range. Measurements under different conditions were highly repeatable, and model error was low in all cases. Significance and Conclusion: SWR depends on modeling the ARFI-induced shear wave as a full vector viscoelastic shear wave resulting from an axisymmetric source; it is agnostic to any specific rheological model. Despite this generality, the model makes three main simplifying assumptions. These results show that the modeling assumptions used in SWR are valid in bovine liver, over a wide frequency band.

Association of Family Member Incarceration During Childhood and Smoking and Unhealthy Drinking Behaviors, Access to Care, and Functional Status Among Adults in the United States.

IMPORTANCE: Incarceration can result in adverse socioeconomic and health consequences for individuals who have been incarcerated; these consequences extend to their children and may have impacts into later adulthood. OBJECTIVE: To examine the association of family member incarceration (FMI) during childhood and smoking and unhealthy drinking behaviors, access to care, and functional status in later adulthood. DESIGN AND PARTICIPANTS: Adults aged 18-64 and ≥ 65 with and without FMI during childhood from 42 states and Washington DC from the 2019-2022 Behavioral Risk Factor Surveillance System. MAIN MEASURES: Having FMI history was defined as "living with anyone during childhood who served time or was sentenced to serve time in a prison, jail, or other correctional facility." Study outcomes included 1) smoking and unhealthy drinking behaviors, 2) access to care (health insurance coverage, care affordability, having a usual source of care, and use of preventive services), and 3) functional status (e.g., having difficulty walking or climbing stairs). KEY RESULTS: After adjusting for demographic characteristics and other adverse childhood experiences, compared to adults without FMI, adults aged 18-64 with FMI were more likely to report any history of smoking or unhealthy drinking (adjusted odds ratio (AOR): 1.19, 95% confidence interval (CI): 1.11-1.28), any access to care problems (AOR: 1.26, 95% CI: 1.12-1.42), and any functional limitations (AOR: 1.18, 95% CI: 1.10-1.28); adults aged ≥ 65 with FMI reported higher likelihood of reporting any smoking or unhealthy drinking behaviors (AOR: 1.23, 95% CI: 1.05-1.43) and impaired functional status (AOR: 1.30, 95% CI: 1.10-1.54). Associations were attenuated after additional adjustment for socioeconomic measures, especially educational attainment, but remained statically significant for multiple outcomes. CONCLUSIONS: FMI during childhood was associated with adverse health-related outcomes for adults of all ages. Developing programs to improve access to education and economic opportunities for adults with FMI may help mitigate the disparities.

High uptake of sympagic organic matter by benthos on an Arctic outflow shelf.

On Arctic shelves, benthic food-webs are tightly linked to overlying primary production. In the seasonal ice zone, sympagic (ice-associated) primary production can be a major source of carbon for the benthos on productive inflow shelves. However, the role of sympagic organic matter is less well-understood in food webs of heavily ice-covered, less- productive outflow shelves, such as the northeast Greenland shelf. Highly branched isoprenoid biomarkers (HBIs) were used to track the relative distribution of sympagic and pelagic organic matter in the water column, sediments, and benthic fauna of the northeast Greenland shelf and fjords. Low pelagic HBI presence throughout the study area indicated a generally low production by pelagic diatoms (at the time of sampling). This was reflected in the benthos, as ~90% of their assimilated carbon was estimated to come from sympagic sources, indicating a benthic food-web highly reliant on sympagic production. This reliance was higher in coastal areas than on the open shelf, where the potentially higher pelagic productivity and shallower water on banks likely increased contributions of pelagic organic matter. As declining ice cover and reduced production of fast-sinking ice algae projected for Arctic shelves will likely result in weaker coupling between ice algae and the benthos, with possible consequences for future benthic-community structure and function.

Interplay between the Glass Transition Temperature, Analyte Diffusion, and Fluorescence Quenching for Detection of Nitro-Group Containing Explosives Using Organic Semiconducting Films.

Efficient detection of chemical analytes using fluorescence-based sensors necessitates an in-depth understanding of the physical interaction between the analyte molecules and the sensor films. This study explores the interplay between the thermal properties of a series of triphenylamine-centered fluorescent dendrimers with different glass transition temperatures (Tg) for detecting nitroaromatic explosives. When exposed to 4-nitrotoluene (pNT) vapors, biphasic diffusion kinetics were observed for all the dendrimers, corresponding to Super Case II kinetics, suggesting rapid film swelling during initial analyte uptake. The diffusion kinetics were further analyzed using a diffusion-relaxation model, where a strong Tg dependence was observed for both the initial concentration-driven diffusion phase and the slower film relaxation phase. Additionally, a difference in kinetics between analyte uptake and release was observed. The photoluminescence (PL) kinetics also showed a Tg dependence, with more efficient PL recovery observed for films composed of dendrimers that had a lower Tg. Rapid quenching of over 40% with little PL recovery was seen in the dendrimer with the highest Tg (107 °C), while a smaller quench with efficient PL recovery was observed in the dendrimer that had a Tg close to room temperature. The results highlight the critical role of the thermal properties of sensor films in achieving rapid and sensitive detection.

A framework for integrating wastewater-based epidemiology and public health.

Wastewater-based epidemiology (WBE) is an environmental approach to monitor community health through the analysis of sewage. The COVID-19 pandemic catalyzed scientists and public health professionals to revisit WBE as a tool to optimize resource allocation to mitigate disease spread and prevent outbreaks. Some studies have highlighted the value of WBE programs that coordinate with public health professionals; however, the details necessary for implementation are not well-characterized. To respond to this knowledge gap, this article documents the framework of a successful WBE program in Arizona, titled Wastewater Analysis for Tactical Epidemiological Response Systems (WATERS), detailing the developed structure and methods of communication that enabled public health preparedness and response actions. This communication illustrates how program operations were employed to reduce outbreak severity. The structure outlined here is customizable and may guide other programs in the implementation of WBE as a public health tool.

Screening and diagnosis of chronic kidney disease among patients living with diabetes: A retrospective cohort study using the Canadian Primary Care Sentinel Surveillance Network.

INTRODUCTION: In Canada, regional evaluations of screening practices for chronic kidney disease (CKD) among people with diabetes highlight areas for improvement; however, national estimates are notably absent. Estimates of CKD incidence often discount the expected decline in eGFR associated with age; age-adaptive thresholds may help account for this. We describe the frequency of screening and diagnosis of CKD among adults with diabetes among a nationally representative primary care cohort. METHODS: In this retrospective cohort study, we used electronic medical record data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). We followed adult patients (18+) with diabetes without CKD at baseline for 5 years starting in 2014. We determined the frequency of ACR and/or eGFR testing over time. We identified incident CKD diagnoses based on eGFR measurements using fixed-threshold and age-adaptive definitions and quantified the incidence proportion and rate. RESULTS: We analysed records from 37,604 patients with diabetes. Only 13% of patients had yearly eGFR and ACR testing for CKD, though roughly 60% had non-yearly use of both tests in 5 years. eGFR testing was performed more frequently than ACR testing (94.1% vs. 76.6% having testing over follow-up). We found increased incidence proportions (14.6 % vs. 6.0%) and rates (33.1 vs. 13.4 diagnoses/1000 person-years) of CKD using the fixed-threshold compared to age-adaptive definitions. CONCLUSIONS: Our study presents the first national understanding of screening practices for CKD among people with diabetes in Canada. In particular, increased use of ACR testing should be encouraged for early detection of changes in kidney function.

Functional patient-reported outcome measures after hip or knee arthroplasty: A systematic review and content analysis using the International Classification of Functioning, Disability and Health (ICF).

OBJECTIVE: This systematic review aimed to identify the existing patient-reported outcome measures (PROMs) used in hip or knee arthroplasty for adults with osteoarthritis and assess their content validity using the modified International Classification of Functioning, Disability and Health (ICF) core set for osteoarthritis (OA). METHOD: Four databases were systematically searched to identify disease or joint-specific PROMs evaluating function after hip or knee arthroplasty. Two reviewers independently evaluated the content of PROMs based on established ICF linking rules. RESULTS: From 449 studies included in this review, 50 PROMs were identified. The mobility chapter of activities and participation was the most common component, followed by sensory function and pain chapter of body function and structure. The most frequent ICF activity and participation categories were d451:going up and down stairs, d4701:using private motorized transportation, d4104:standing, and d4154:maintaining a standing position. However, 11 ICF categories of the modified OA coreset were not captured in any PROMs. This ICF-based content analysis of PROMs revealed that included activity and participation categories vary widely, with little overlap between PROMs. The Knee injury and Osteoarthritis Outcome Score and Hip disability and Osteoarthritis Outcome Score had the most coverage for activity and participation (36.7%). CONCLUSION: Even though our search identified 50 specific PROMs, there remain gaps in content related to activity and participation coverage. By providing a content analysis of the PROMs used after hip or knee arthroplasty, this study may help clinicians select PROMs based on covered categories and relevant clinical objectives.

Withdrawn: A systematic review of autopsy findings in deaths after COVID-19 vaccination.

This Article-in-Press has been withdrawn at the request of the Editors-in-Chief. Members of the scientific community raised concerns about this Article-in-Press following its posting online. The concerns encompassed. • Inappropriate citation of references. • Inappropriate design of methodology. • Errors, misrepresentation, and lack of factual support for the conclusions. • Failure to recognise and cite disconfirming evidence. The concerns were shared with the authors, who prepared a response and submitted a revised manuscript for consideration by the journal. In consideration of the extent of the concerns raised and the responses from the authors, the journal sent the revised manuscript to two independent peer-reviewers. The peer-reviewers concluded that the revised manuscript did not sufficiently address the concerns raised by the community and that it was not suitable for publication in the journal. The authors disagree with this withdrawal and dispute the grounds for it. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal.

Peer Support Interventions for People With CKD: A Scoping Review.

RATIONALE & OBJECTIVE: Formalized peer support is a promising approach for addressing the emotional and practical needs of people living with chronic kidney disease (CKD). We aimed to systematically identify and summarize peer support interventions studied in individuals with CKD with or without kidney replacement therapy (KRT). SOURCES OF EVIDENCE: We searched electronic databases and grey literature sources in March 2023. ELIGIBILITY CRITERIA: Studies of any design were eligible if they reported sufficient detail on peer support interventions and outcomes for adults with CKD with or without KRT and/or their caregivers. CHARTING METHODS: We extracted information on study and intervention characteristics and reported outcomes using established frameworks. We summarized quantitative data descriptively and qualitative data thematically. Our approach observed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. RESULTS: We included 77 studies describing 56 unique peer support interventions. Most reports were program evaluations (39%) or randomized controlled trials (27%) published after 2013. Two thirds of interventions focused on in-centre hemodialysis or mixed CKD populations, and three quarters were integrated within a kidney care clinic or program. Whereas most peer interactions centered on informational support, few programs offered focused support in areas such as transplant navigation or dialysis modality selection. Only one third of outcomes were assessed against a comparator group, with results suggesting improvements in psychological health with peer support. LIMITATIONS: Heterogeneity of included studies; lack of rigorous program evaluation. CONCLUSIONS: This review suggests recent growth in peer support programming with a variety of formats and delivery methods to address the diverse needs of people living with kidney disease. Notable gaps in peer support availability for transplant and home dialysis recipients and the lack of rigorous evaluations present opportunities to expand the reach and impact of peer support in the kidney care context.

Association of prenatal vitamin E levels with child asthma and wheeze.

BACKGROUND: We investigated the individual and interaction effects of maternal plasma 𝛂- and ϒ-tocopherol levels (vitamin E isomers) on child asthma and wheeze at age 8-9. METHODS: Mother-child dyads were enrolled between 2006 and 2011 into the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) prenatal cohort. Maternal second-trimester samples were analyzed for tocopherol and lipid concentrations. We assessed child asthma/wheeze using the International Study of Asthma and Allergies in Childhood (ISAAC) and other self-reported Ent wheeze. In multivariable logistic regression analyses, we assessed associations between vitamin E isomers and child asthma/wheeze outcomes (n = 847 mother-child dyads) and tested for prespecified interaction terms. RESULTS: Median cholesterol-corrected tocopherol levels (interquartile range (IQR)) were 5.0 (4.3-5.7) and 0.8 (0.7-0.9) (umol/mmol) for 𝛂- and ϒ-tocopherol, respectively. Associations between 𝛂-tocopherol and asthma outcome variables were inverse but not statistically significant. In contrast, for ϒ-tocopherol, associations were in the positive direction, but also nonsignificant. Interactions analysis between tocopherols did not reach statistical significance for any outcome. Among children of women with a history of asthma, the likelihood of ever asthma in the child appears to be decreasing with increasing maternal 𝛂-tocopherol levels, whereas this trend was not observed among those without a history of asthma (p-interaction = .05). CONCLUSION: We observed no associations for prenatal 𝛂- or ϒ-tocopherol concentrations with child asthma/wheeze. We detected some evidence of effect modification by maternal asthma history in associations between 𝛂-tocopherol and child asthma.

Chameleonic Cages: Encapsulation of Anionic, Neutral, and Cationic Guest Species within [Fe4L4]8+ Tetrahedral Cages Synthesised from the tris(4-aminophenyl)phosphate pro-Ligand.

An adaptable Fe(II) tetrahedral cage, [Fe4L4][BF4]8 (L = tris(4-(((E)-pyridin-2-ylmethylene)amino)phenyl) phosphate), has been synthesised via self-assembly. By modulating the orientation of its pendant P=O groups, the cage was found to be capable of encapsulating anionic, neutral, and cationic guests, which was confirmed in the solid state via single-crystal X-ray diffraction (SCXRD) and in solution by high-resolution mass spectroscopy (HR-MS), as well as by NMR (1H, 19F, 31P) studies where possible.

The nonphototrophic hypocotyl 3 (NPH3) domain protein NRL5 is a trafficking-associated GTPase essential for drought resistance.

The mechanisms of plant drought resistance are unclear but may involve membrane trafficking and metabolic reprogramming, including proline accumulation. Forward genetic screening using a proline dehydrogenase 1 (ProDH1) promoter:reporter identified a drought hypersensitive mutant with a single-amino acid substitution (P335L) in the nonphototrophic hypocotyl 3 (NPH3) domain of NPH3/root phototropism 2-like 5 (NRL5)/naked pins in Yucca 8 (NPY8). Further experiments found that NRL5 and other NPH3 domain proteins are guanosine triphosphatases (GTPases). NRL5, but not NRL5P335L, interacted with the RABE1c and RABH1b GTPases and the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) Vesicle-Associated Membrane Protein (VAMP)721/722. These proteins controlled NRL5 localization and connection to trafficking while also being genetically downstream of, and potentially regulated by, NRL5. These data demonstrate that NRL5-mediated restraint of proline catabolism is required for drought resistance and also reveal unexpected functions of the NPH3 domain such that the role of NPH3 domain proteins in signaling, trafficking, and cellular polarity can be critically reevaluated.