Mode mixing and losses in misaligned microcavities.

We present a study on the optical losses of Fabry-Pérot cavities subject to realistic transverse mirror misalignment. We consider mirrors of the two most prevalent surface forms: idealised spherical depressions, and Gaussian profiles generated by laser ablation. We first describe the mode mixing phenomena seen in the spherical mirror case and compare to the frequently-used clipping model, observing close agreement in the predicted diffraction loss, but with the addition of protective mode mixing at transverse degeneracies. We then discuss the Gaussian mirror case, detailing how the varying surface curvature across the mirror leads to complex variations in round trip loss and mode profile. In light of the severe mode distortion and strongly elevated loss predicted for many cavity lengths and transverse alignments when using Gaussian mirrors, we suggest that the consequences of mirror surface profile are carefully considered when designing cavity experiments.

Optogenetically-induced multimerization of the dopamine transporter increases uptake and trafficking to the plasma membrane.

The dopamine transporter (DAT) is essential for the reuptake of the released neurotransmitter dopamine (DA) in the brain. Psychostimulants, methamphetamine and cocaine, have been reported to induce the formation of DAT multimeric complexes in vivo and in vitro. The interpretation of DAT multimer function has been primarily in the context of compounds that induce structural and functional modifications of the DAT, complicating the understanding of the significance of DAT multimers. To examine multimerization in the absence of DAT ligands as well as in their presence, we developed a novel, optogenetic fusion chimera of cryptochrome 2 and DAT with an mCherry fluorescent reporter (Cry2-DAT). Using blue light to induce Cry2-DAT multimeric protein complex formation, we were able to simultaneously test the functional contributions of DAT multimerization in the absence or presence of substrates or inhibitors with high spatiotemporal precision. We found that blue light-stimulated Cry2-DAT multimers significantly increased IDT307 uptake and MFZ 9-18 binding in the absence of ligands as well as after methamphetamine and nomifensine treatment. Blue light-induced Cry2-DAT multimerization increased colocalization with recycling endosomal marker Rab11 and had decreased presence in Rab5-positive early endosomes and Rab7-positive late endosomes. Our data suggest that the increased uptake and binding results from induced and rapid trafficking of DAT multimers to the plasma membrane. Our data suggest that DAT multimers may function to help maintain DA homeostasis.

Yttrium-90 Hepatic Radioembolization for Advanced Chemorefractory Metastatic Colorectal Cancer: Survival Outcomes Based on Right- Versus Left-Sided Primary Tumor Location.

BACKGROUND. Primary colon cancer location affects survival of patients with metastatic colorectal cancer (mCRC). Outcomes based on primary tumor location after salvage hepatic radioembolization with 90Y resin microspheres are not well studied. OBJECTIVE. The objectives of this study are to assess the survival outcomes of patients with advanced chemorefractory mCRC treated with 90Y radioembolization, as stratified by primary tumor location, and to explore potential factors that are predictive of survival. METHODS. A total of 99 patients who had progressive mCRC liver metastases while receiving systemic therapy and who were treated with 90Y radioembolization at a single center were retrospectively analyzed. For 89 patients, tumor response on the first imaging follow-up examination (CT or MRI performed at a mean [± SD] of 1.9 ± 0.9 months after 90Y radioembolization) was evaluated using RECIST. Overall survival (OS), OS after 90Y radioembolization, and hepatic progression-free survival (PFS) were calculated using the Kaplan-Meier method. Outcomes and associations of outcomes with tumor response were compared between patients with left- and right-sided tumors. RESULTS. A total of 74 patients had left-sided colon cancer, and 25 patients had right-sided colon cancer. Median OS from the time of mCRC diagnosis was 37.2 months, median OS after 90Y radioembolization was 5.8 months, and median hepatic PFS was 3.3 months. Based on RECIST, progressive disease on first imaging follow-up was observed in 38 patients (43%) after 90Y radioembolization and was associated with shorter OS after 90Y radioembolization compared with observation of disease control on first imaging follow-up (4.0 vs 10.5 months; p < .001). Patients with right-sided primary tumors showed decreased median OS after 90Y radioembolization compared with patients with left-sided primary tumors (5.4 vs 6.2 months; p = .03). Right- and left-sided primary tumors showed no significant difference in RECIST tumor response, hepatic PFS, or extrahepatic disease progression (p > .05). Median survival after 90Y radioembolization was significantly lower among patients with progressive disease than among those with disease control in the group with left-sided primary tumors (4.2 vs 13.9 months; p < .001); however, this finding was not observed in the group with right-sided primary tumors (3.3 vs 7.2 months; p = .05). CONCLUSION. Right-sided primary tumors were independently associated with decreased survival among patients with chemorefractory mCRC after 90Y radioembolization, despite these patients having a similar RECIST tumor response, hepatic PFS, and extrahepatic disease progression compared with patients with left-sided primary tumors. CLINICAL IMPACT. Primary colon cancer location impacts outcomes after salvage 90Y radioembolization and may help guide patient selection.

High-Rate, High-Fidelity Entanglement of Qubits Across an Elementary Quantum Network.

We demonstrate remote entanglement of trapped-ion qubits via a quantum-optical fiber link with fidelity and rate approaching those of local operations. Two ^{88}Sr^{+} qubits are entangled via the polarization degree of freedom of two spontaneously emitted 422 nm photons which are coupled by high-numerical-aperture lenses into single-mode optical fibers and interfere on a beam splitter. A novel geometry allows high-efficiency photon collection while maintaining unit fidelity for ion-photon entanglement. We generate heralded Bell pairs with fidelity 94% at an average rate 182 s^{-1} (success probability 2.18×10^{-4}).

Worsening pulmonary outcomes during sex reassignment therapy in a transgender female with cystic fibrosis (CF) and asthma/allergic bronchopulmonary aspergillosis: a case report.

BACKGROUND: Cystic Fibrosis (CF) is a hereditary pulmonary and extra-pulmonary disease that occurs equally in men and women. However, a difference in morbidity and mortality rates between the sexes has been long documented. Similarly, a sex-disparity in disease severity has been reported in asthma as well. Studies done to date point to estrogen as a possible cause of this sex disparity in pulmonary outcomes in both conditions. CASE PRESENTATION: Here, we describe a case of a patient with CF and asthma/allergic bronchopulmonary aspergillosis (ABPA) undergoing sex reassignment therapy (male-to-female) and the negative impact it had on her lung function and frequency of pulmonary exacerbations in the context of increasing doses of exogenous estrogen. CONCLUSIONS: This case raises the possibility of a link between estrogen and worsening pulmonary outcomes and the need for further studies into transgender individuals with CF and/or asthma/ABPA as well as those undergoing high dose estrogen therapy for other indications.

Lapatinib-induced annexin A6 upregulation as an adaptive response of triple-negative breast cancer cells to EGFR tyrosine kinase inhibitors.

The epidermal growth factor receptor (EGFR) is a major oncogene in triple-negative breast cancer (TNBC), but the use of EGFR-targeted tyrosine kinase inhibitors (TKI) and therapeutic monoclonal antibodies is associated with poor response and acquired resistance. Understanding the basis for the acquired resistance to these drugs and identifying biomarkers to monitor the ensuing resistance remain a major challenge. We previously showed that reduced expression of annexin A6 (AnxA6), a calcium-dependent membrane-binding tumor suppressor, not only promoted the internalization and degradation of activated EGFR but also sensitized TNBC cells to EGFR-TKIs. Here, we demonstrate that prolong (>3 days) treatment of AnxA6-low TNBC cells with lapatinib led to AnxA6 upregulation and accumulation of cholesterol in late endosomes. Basal extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation was EGFR independent and significantly higher in lapatinib-resistant MDA-MB-468 (LAP-R) cells. These cells were more sensitive to cholesterol depletion than untreated control cells. Inhibition of lapatinib-induced upregulation of AnxA6 by RNA interference (A6sh) or withdrawal lapatinib from LAP-R cells not only reversed the accumulation of cholesterol in late endosomes but also led to enrichment of plasma membranes with cholesterol, restored EGFR-dependent activation of ERK1/2 and sensitized the cells to lapatinib. These data suggest that lapatinib-induced AnxA6 expression and accumulation of cholesterol in late endosomes constitute an adaptive mechanism for EGFR-expressing TNBC cells to overcome prolong treatment with EGFR-targeted TKIs and can be exploited as an option to inhibit and/or monitor the frequently observed acquired resistance to these drugs.

Probing Qubit Memory Errors at the Part-per-Million Level.

Robust qubit memory is essential for quantum computing, both for near-term devices operating without error correction, and for the long-term goal of a fault-tolerant processor. We directly measure the memory error ε_{m} for a ^{43}Ca^{+} trapped-ion qubit in the small-error regime and find ε_{m}<10^{-4} for storage times t≲50 ms. This exceeds gate or measurement times by three orders of magnitude. Using randomized benchmarking, at t=1 ms we measure ε_{m}=1.2(7)×10^{-6}, around ten times smaller than that extrapolated from the T_{2}^{*} time, and limited by instability of the atomic clock reference used to benchmark the qubit.

'We've made the best of it. But we do not have a normal life': families' experiences of tuberous sclerosis complex and seizure management.

BACKGROUND: Tuberous sclerosis complex (TSC) is a complex multisystem genetic disorder. Approximately 84% of people with TSC have epilepsy. However, there is little literature available regarding families' experiences with TSC and seizure management. Therefore, the aim of the current study was to explore families' positive and negative experiences, and attitudes towards TSC, epilepsy and medical management of seizures. METHODS: Framework analysis informed an open exploration of families' experiences with TSC, epilepsy and medical management of seizures. Using structured interviews, 11 parents of people with TSC and 2 people with TSC were interviewed, providing the data set for transcription and thematic analysis. RESULTS: 'TSC rules our life' overarched three subordinate themes: 'Our normal', 'Burnout' and 'Seizure management has given us our life back'. Families had to adapt to the normality of needing to constantly supervise their child even as they become an adult. They express a feeling of fear particularly of seizures, and this has impact throughout the family. There are frequent expressions of exhaustion and struggling to fight for access and support. There are some positives and cautious hope with the gaining of control from seizures as being able to predict or plan improves activity and participation. These interviews provided a rich insight into the lives of those with TSC and their families. CONCLUSION: There are exciting developments with respect to scientific understanding of the pathophysiology of TSC, which opens opportunity for new treatments. Holistic family centred health care and practical support (e.g. opportunities for parental respite) is as important as medical intervention. As TSC is such a complex condition, there is a need for specialist clinics and TSC-specific research.

PML-Nuclear Bodies Regulate the Stability of the Fusion Protein Dendra2-Nrf2 in the Nucleus.

BACKGROUND/AIMS: Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine-zipper transcription factor essential for cellular responses to oxidative stress. Degradation of Nrf2 in the cytoplasm, mediated by Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase and the proteasome, is considered the primary pathway controlling the cellular abundance of Nrf2. Although the nucleus has been implicated in the degradation of Nrf2, little information is available on how this compartment participates in degrading Nrf2. METHODS: Here, we fused the photoconvertible fluorescent protein Dendra2 to Nrf2 and capitalized on the irreversible change in color (green to red) that occurs when Dendra2 undergoes photoconversion to study degradation of Dendra2-Nrf2 in single live cells. RESULTS: Using this approach, we show that the half-life (t1/2) of Dendra2-Nrf2 in the whole cell, under homeostatic conditions, is 35 min. Inhibition of the proteasome with MG-132 or induction of oxidative stress with tert-butylhydroquinone (tBHQ) extended the half-life of Dendra2-Nrf2 by 6- and 28-fold, respectively. By inhibiting nuclear export using Leptomycin B, we provide direct evidence that degradation of Nrf2 also occurs in the nucleus and involves PML-NBs (Promyelocytic Leukemia-nuclear bodies). We further demonstrate that co-expression of Dendra2-Nrf2 and Crimson-PML-I lacking two PML-I sumoylation sites (K65R and K490R) changed the decay rate of Dendra2-Nrf2 in the nucleus and stabilized the nuclear derived Nrf2 levels in whole cells. CONCLUSION: Altogether, our findings provide direct evidence for degradation of Nrf2 in the nucleus and suggest that modification of Nrf2 in PML nuclear bodies contributes to its degradation in intact cells.

The role of citizen science in addressing grand challenges in food and agriculture research.

The power of citizen science to contribute to both science and society is gaining increased recognition, particularly in physics and biology. Although there is a long history of public engagement in agriculture and food science, the term 'citizen science' has rarely been applied to these efforts. Similarly, in the emerging field of citizen science, most new citizen science projects do not focus on food or agriculture. Here, we convened thought leaders from a broad range of fields related to citizen science, agriculture, and food science to highlight key opportunities for bridging these overlapping yet disconnected communities/fields and identify ways to leverage their respective strengths. Specifically, we show that (i) citizen science projects are addressing many grand challenges facing our food systems, as outlined by the United States National Institute of Food and Agriculture, as well as broader Sustainable Development Goals set by the United Nations Development Programme, (ii) there exist emerging opportunities and unique challenges for citizen science in agriculture/food research, and (iii) the greatest opportunities for the development of citizen science projects in agriculture and food science will be gained by using the existing infrastructure and tools of Extension programmes and through the engagement of urban communities. Further, we argue there is no better time to foster greater collaboration between these fields given the trend of shrinking Extension programmes, the increasing need to apply innovative solutions to address rising demands on agricultural systems, and the exponential growth of the field of citizen science.

Selective Activation of N,N'-Diacyl Rhodamine Pro-fluorophores Paired with Releasing Enzyme, Porcine Liver Esterase (PLE).

This study reports the synthesis and testing of a family of rhodamine pro-fluorophores and an enzyme capable of converting pro-fluorophores to Rhodamine 110. We prepared a library of simple N,N'-diacyl rhodamines and investigated porcine liver esterase (PLE) as an enzyme to activate rhodamine-based pro-fluorophores. A PLE-expressing cell line generated an increase in fluorescence rapidly upon pro-fluorophore addition demonstrating the rhodamine pro-fluorophores are readily taken up and fluorescent upon PLE-mediated release. Rhodamine pro-fluorophore amides trifluoroacetamide (TFAm) and proponamide (PAm) appeared to be the best substrates using a cell-based assay using PLE expressing HEK293. Our pro-fluorophore series showed diffusion into live cells and resisted endogenous hydrolysis. The use of our engineered cell line containing the exogenous enzyme PLE demonstrated the rigorousness of amide masking when compared to cells not containing PLE. This simple and selective pro-fluorophore rhodamine pair with PLE offers the potential to be used in vitro and in vivo fluorescence based assays.

Understanding frames: A UK survey of parents and professionals regarding the use of standing frames for children with cerebral palsy.

BACKGROUND: Standing frames are used for children with cerebral palsy (CP). They may improve body structure and function (e.g., reducing risk of hip subluxation, and improving bladder and bowel function), improving activity (e.g., motor abilities) and participation (e.g., interaction with peers), but there is little evidence that they do. We aimed to identify current UK standing frame practice for children with CP and to understand stakeholder views regarding their clinical benefits and challenges to use. METHOD: Three populations were sampled: clinicians prescribing standing frames for children with CP (n = 305), professionals (health and education) working with children with CP who use standing frames (n = 155), and parents of children with CP who have used standing frames (n = 91). Questionnaires were developed by the co-applicant group and piloted with other professionals and parents of children with CP. They were distributed online via clinical and parent networks across the UK. RESULTS: Prescribing practice was consistent, but achieving the prescribed use was not always possible. Respondents in all groups reported the perceived benefits of frames, which include many domains of the International Classification of Functioning Disability and Health for Children and Youth. Challenges of use are related to physical space and child-reported pain. CONCLUSIONS: These survey findings provide information from key stakeholders regarding current UK standing frame practice.

Understanding frames: A qualitative study of young people's experiences of using standing frames as part of postural management for cerebral palsy.

BACKGROUND: Consensus opinion supports standing frame use as part of postural management for nonambulant young people with cerebral palsy. Although the rationale for standing frame use and the associated challenges have been described, little attention has been given to the users' experiences. The aim of the current study was to explore young people's positive and negative experiences, and attitudes regarding standing frame use. METHODS: Framework analysis informed an open exploration of young people's opinions of standing frames. Using semistructured interviews, 12 young people with cerebral palsy (6 female) were interviewed, providing the data set for transcription and thematic analysis. FINDINGS: The first theme "attitudes to standing frames" describes the young people's understanding of why they use standing frames. Although standing frames can be painful, some young people believe they should be endured to improve their body structure and function. There were mixed views about the impact standing frames have socially, with some young people feeling excluded from their peers, and others feeling as though standing frames helped them "fit in." Some young people are not offered a choice about how and when they use their standing frame. The second theme "challenges of standing frame use" highlights the issues with standing frame use such as manual handling, interference from siblings, and the lack of aesthetically pleasing standing frame designs. CONCLUSIONS: Young people report benefits related to choice, pain relief, and participation but can also cause pain, discomfort, and reduced independence and participation. Healthcare professionals should have open, informative conversations about potential benefits and challenges of standing frames on all aspects of the young people's lives, including participation and activity.

An optical method for characterizing carbon content in ceramic pot filters.

Ceramic pot filter (CPF) technology is a relatively common means of household water treatment in developing areas, and performance characteristics of CPFs have been characterized using production CPFs, experimental CPFs fabricated in research laboratories, and ceramic disks intended to be CPF surrogates. There is evidence that CPF manufacturers do not always fire their products according to best practices and the result is incomplete combustion of the pore forming material and the creation of a carbon core in the final CPFs. Researchers seldom acknowledge the existence of potential existence of carbon cores, and at least one CPF producer has postulated that the carbon may be beneficial in terms of final water quality because of the presence of activated carbon in consumer filters marketed in the Western world. An initial step in characterizing the presence and impact of carbon cores is the characterization of those cores. An optical method which may be more viable to producers relative to off-site laboratory analysis of carbon content has been developed and verified. The use of the optical method is demonstrated via preliminary disinfection and flowrate studies, and the results of these studies indicate that the method may be of use in studying production kiln operation.

'At the end of the day, it is more important that he stays happy': an interpretative phenomenological analysis of people who have a sibling with 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome. However, there is little research examining the effect of this multisystem disorder on the family, particularly siblings. The current study was a phenomenological exploration of sense-making in siblings of a person with 22q11.2DS. METHOD: Interpretative phenomenological analysis informed a detailed and open examination of being a sibling of a person with 22q11.2DS. Using in-depth semistructured interviews, five typically developing siblings (two men, three women) of people with 22q11.2DS were individually interviewed, providing the data set for transcription and thematic analysis. RESULTS: The theme 'They are the priority' overarched two subordinate themes that emerged from participants' descriptions of the struggle with acceptance and finding positive meaning. Participants oscillated between conflicting feelings about their sibling with 22q11.2DS always taking centre stage. For example, they felt anger, guilt and resentment; yet, they also embraced patience, empathy and gratitude. CONCLUSIONS: This phenomenological study provides a foundation for future research relating to 22q11.2DS and fostering family wellbeing, particularly around acceptance and psychological growth. The siblings in this study actively withdrew from their family to allow prioritisation of their affected sibling. However, this does not mean that their needs should be overlooked. There are easily accessible resources to support siblings of individuals with disabilities, and it is important for health professionals and parents to consider these options.

Dopamine Transporter Activity Is Modulated by α-Synuclein.

The duration and strength of the dopaminergic signal are regulated by the dopamine transporter (DAT). Drug addiction and neurodegenerative and neuropsychiatric diseases have all been associated with altered DAT activity. The membrane localization and the activity of DAT are regulated by a number of intracellular proteins. α-Synuclein, a protein partner of DAT, is implicated in neurodegenerative disease and drug addiction. Little is known about the regulatory mechanisms of the interaction between DAT and α-synuclein, the cellular location of this interaction, and the functional consequences of this interaction on the basal, amphetamine-induced DAT-mediated dopamine efflux, and membrane microdomain distribution of the transporter. Here, we found that the majority of DAT·α-synuclein protein complexes are found at the plasma membrane of dopaminergic neurons or mammalian cells and that the amphetamine-mediated increase in DAT activity enhances the association of these proteins at the plasma membrane. Further examination of the interaction of DAT and α-synuclein revealed a transient interaction between these two proteins at the plasma membrane. Additionally, we found DAT-induced membrane depolarization enhances plasma membrane localization of α-synuclein, which in turn increases dopamine efflux and enhances DAT localization in cholesterol-rich membrane microdomains.

Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates.

OBJECTIVES: CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage regimens. METHODS: A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS infections were developed. The results were then bridged to neonates by use of population pharmacokinetic techniques and Monte Carlo simulations. RESULTS: There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels. The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg ·â€Šh/L. Simulations predicted that neonates <29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups. CONCLUSIONS: The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance. This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to take into a randomized controlled trial.

Resolved-Sideband Laser Cooling in a Penning Trap.

We report the laser cooling of a single ^{40}Ca^{+} ion in a Penning trap to the motional ground state in one dimension. Cooling is performed in the strong binding limit on the 729-nm electric quadrupole S_{1/2}↔D_{5/2} transition, broadened by a quench laser coupling the D_{5/2} and P_{3/2} levels. We find the final ground-state occupation to be 98(1)%. We measure the heating rate of the trap to be very low with n[over ¯][over ˙]≈0.3(2) s^{-1} for trap frequencies from 150-400 kHz, consistent with the large ion-electrode distance.

Lighter and heavier initial loads yield similar gains in strength when employing a progressive wave loading scheme.

Progressive wave loading strategies are common within strength and conditioning practice. The purpose of this study was to contribute to the understanding of this strategy by evaluating the effectiveness of 2 wave loading bench press training programmes that differed only in the initial load that was used to start the first wave. Thirty-four resistance-trained men were divided into 2 groups and performed 2 training sessions each week for 20 weeks. One session consisted of 6 sets of 2 repetitions, while the other consisted of 5 sets of 5 repetitions. The load used was incremented by 2.5% of one repetition maximum (1RM) each week until the subject could no longer complete the programmed repetitions. At this point, the load was decreased, and then started to ascend again. The initial loads for the 2 sessions were 87.5% and 80% 1RM respectively for the heavier group, and for the lighter group were 82.5% and 75% 1RM. The subjects experienced a significant improvement in their bench press performance (higher load group: pre test = 106.5 kg ± 14.6, post test = 112.2 kg ± 12.4, p ≤ 0.05; lower load group: pre test = 105.7 kg ± 14.1, post test = 114.3 kg ± 11.0, p ≤ 0.05), but there was no difference in the magnitude of the improvment between the two groups. These results tend to support the common practical recommendation to start with a lighter load when employing a progressive wave loading strategy, as such a strategy yields similar improvements in performance with a lower level of exertion in training.