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The performance of all active photonic devices today is greatly limited by loss. Here, we show that one can engineer a low loss path in a metal-clad lossy multi-mode waveguide while simultaneously achieving high-performance active photonic devices. We leverage non-Hermitian systems operating beyond the exceptional point to enable the redistribution of losses in a multi-mode photonic waveguide. Consequently, our multi-mode waveguide offers low propagation losses for fundamental mode while other higher order modes experience prohibitively high losses. Furthermore, we show an application of this non-Hermitian waveguide platform in designing power-efficient thermo-optic phase shifters with significantly faster response times than conventional silicon-based thermo-optic phase shifters. Our device achieves a propagation loss of less than 0.02 dB μm−1 for our non-Hermitian waveguide-based phase shifters with high performance efficiency of P π ⋅ τ = 19.1 mW μs. In addition, our phase shifters have significantly faster response time (rise/fall time), τ ≈ 1.4 μs, compared to traditional silicon based thermo-optic phase shifters.

Umakant Dave,1 Simon D Taylor-Robinson2 1Department of Gastroenterology, Morriston Hospital, Swansea, Wales, SA6 6NL, UK; 2Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital Campus, London, W2 1NY, UKCorrespondence: Simon D Taylor-Robinson, Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital Campus, London, W2 1NY, UK, Tel +44 203 312 6254, Email str338333@gmail.comBackground: The practice of medicine is becoming increasingly more stressful, owing to technological development, increased expectations, infrastructure deficiencies, lack of resources and healthcare systems that are struggling to cope in the face of the COVID-19 pandemic around the world.Objective: In this article, we explore ways to reduce stress and improve resilience in the work place in order to enhance wellbeing in the medical profession, but also ultimately to protect patient safety.Synopsis: We discuss attention to regular mealtimes, protected sleep and daily exercise, together with consideration of mindfulness, gratefulness, self-compassion, self-care and being part of supportive networks as ways to reduce stress.Conclusion: While such techniques are not guaranteed to mitigate stress, psychology studies have shown that awareness of and attention to these components of a healthy lifestyle have the potential to reduce the adverse effects of increasing professional demands.Keywords: mindfulness, burnout, self-care, self-compassion, wellbeing, gratefulness

Neil Hawkes,1,2 Umakant Dave,3 Mesbah Rahman,2,3 Dafydd Richards,3 Mahmud Hasan,4,5 AHM Rowshon,4 Faruque Ahmed,4,6 M Masudur Rahman,6 MG Kibria,6 Phedra Dodds,7 Bethan Hawkes,8 Stuart Goddard,9 Imdadur Rahman,10 Peter Neville,1 Mark Feeney,11 Gareth Jenkins,12 Keith Lloyd,12 Krish Ragunath,13 Cathryn Edwards,2,11 Simon D Taylor-Robinson14 1Department of Gastroenterology, Cwm Taf Morgannwg University Health Board, Llantrisant, South Wales, UK; 2British Society of Gastroenterology Central Office, London, UK; 3Department of Gastroenterology, Swansea Bay University Health Board, Swansea, UK; 4Office of the Central Secretariat, Bangladesh Gastroenterology Society, Dhaka, Bangladesh; 5Office of Central Secretariat, Gastroliver Foundation, Dhaka, Bangladesh; 6Department of Gastroenterology, Sheikh Russel National Gastroliver Institute and Hospital, Dhaka, Bangladesh; 7Department of Endoscopy Nursing, Office of the JAG GRS Team, Powys Health Board, Brecon, UK; 8Office of the Wales Cancer Network Pathway, Welsh Cancer Network, Cardiff, UK; 9Welsh Institute of Minimal Access Therapy, Cardiff MediCentre, Welsh Institute for Minimal Access Therapy, Cardiff University, Cardiff, UK; 10Department of Gastroenterology, Southampton NHS Trust, Southampton, UK; 11Department of Gastroenterology and Liver Medicine, Torbay and South Devon NHS Foundation Trust, Devon, UK; 12Faculty of Health and Life Sciences, Medicine, Swansea University, Swansea, UK; 13Office of the Provost, Faculty of Health Sciences, Bentley Campus, Curtin Medical School, Curtin University, Perth, Western Australia, Australia; 14Department of Surgery and Cancer, Imperial College London, London, UKCorrespondence: Neil Hawkes Email neil.hawkes@wales.nhs.ukAbstract: The British Society of Gastroenterology (BSG) and the Bangladesh Gastroenterology Society (BGS) have collaborated on an endoscopy training programme, which has grown up over the past decade from a small scheme borne out of the ideas of consultant gastroenterologists in Swansea, South Wales (United Kingdom) to improve gastroenterology services in Bangladesh to become a formalised training programme with broad reach. In this article, we document the socioeconomic and historical problems that beset Bangladesh, the current training needs of doctors and how the BSG-BGS collaboration has made inroads into changing outcomes both for gastroenterologists in Bangladesh, but also for the populations they serve.Keywords: endoscopy training, Bangladesh, training programmes, gastroenterology training

One of the sustainable alternatives to Portland cement is geopolymer concrete consisting of industrial waste. Practical application of geopolymer concrete is restricted as it requires the use of high temperature to develop compressive strength. This study aims to develop a mixture design for geopolymer prestressed concrete specifically designed to take prestressing force using ambient curing technique and compare its performance with the same grade of Portland cement concrete mix. As ambient curing technique is used for geopolymer concrete hence a combination of blast furnace slag and fly ash is taken as source materials and due to ease of availability and economy, sodium hydroxide and silicate are chosen as activators. After several trial mixtures, M 40 grade of geopolymer concrete is developed using an equal proportion of fly ash and ground granulated blast furnace slag (GGBFS) as source material. GGBFS provides early strength at ambient curing in geopolymer concrete and hence was incorporated with fly ash. 3 ply of 3 mm diameter bars were used as pre-tensioning wire. Load v/s deflection graph for non-prestressed geopolymer concrete beams and beams with same grade Portland cement concrete show that the load-carrying capacity of both beams was at par. It was also observed that prestressed geopolymer concrete beams which were cured under ambient curing developed sufficient strength and were equally capable of carrying the load as compared to Portland cement concrete beams. Load carrying capacity increased in prestressed Portland cement concrete beams increased by 78% while in prestressed geopolymer concrete beams the increase was 83% and also the deflection of both prestressed beams was more compared to non-prestressed beams. This indicates that sustainable material can be effectively utilized in prestressing work without comprising on strength.

Umakant Dave,1 Anjali Dave,2 Simon David Taylor-Robinson3 1Department of Gastroenterology, Morriston Hospital, Swansea, Wales SA6 6NL, UK; 2Department of Psychology, Birmingham University, Birmingham B15 2TT, UK; 3Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital Campus, London W2 1NY, UKCorrespondence: Simon David Taylor-RobinsonDepartment of Surgery and Cancer, Imperial College London, St Mary’s Hospital Campus, London W2 1NY, UKTel +44 203 312 6254Email str338333@gmail.comBackground: Work-related stress is becoming an increasingly recognised occupational hazard that can have detrimental effects on the health of both patient and doctor. The practice of gastroenterology not only includes the demands of clinics and in-patient work faced by other medical specialities but also the additional burden of complex, and often high-risk, endoscopic interventions. Mindfulness, a secular form of meditation, can relieve stress, even if only practiced for a few minutes a day.Methods and Results: We present a personal perspective of the burnout experienced in stressful gastroenterology careers and the personal use of mindfulness in the daily routine to provide a source of calm when surrounded by many different pressures. We review some of the literature exploring the role of mindfulness in clinical practice with an emphasis on gastroenterology. While the practice of mindfulness is not designed to obviate immediacy and quick decisions in a rapidly changing clinical environment, it has been held widely useful to mitigate the stress involved in making those decisions.Conclusion: Practicing mindfulness, meditation and mindful living offers many advantages to gastroenterologists’ wellbeing as well improved patient care. We advocate its teaching to both gastroenterology trainees and consultants who are not familiar with the technique.Keywords: mindfulness, gastroenterology, stress, meditation, wellbeing

The strong nonlinear response of silicon photonic nanowire waveguides allows for the integration of nonlinear optical functions on a chip. However, the detrimental nonlinear optical absorption in silicon at telecom wavelengths limits the efficiency of many such experiments. In this review, several approaches are proposed and demonstrated to overcome this fundamental issue. By using the proposed methods, we demonstrate amongst others supercontinuum generation, frequency comb generation, a parametric optical amplifier, and a parametric optical oscillator.

INTRODUCTION: hospital-acquired infections (HAIs) constitute a serious global public health challenge, causing great suffering to many people across the globe at any given time. This study ascertains the knowledge of health professionals on the challenge and their compliance with infection control measures. METHODS: validated questionnaires were administered to 660 health professionals and supported with face-to-face interview. Data were analyzed using Statistical Package for Social Sciences (SPSS) version 16.0 (SPSS Inc, USA). Chi-square was used to test association between the independent and the outcome variables. Cut-off point for statistical significance was 5% (p value=0.05). RESULTS: UTIs (61.4%) followed by hospital-acquired pneumonia (55.6%) were known to be the most prevalent HAIs in government hospitals while staphylococcus aureus (54.4%) was reported the most microbial agent. In private health facilities, Hospital-acquired Pneumonia was known to be the most common (66.1%) while pseudomonas aeruginosa was the most reported culprit. HAIs were reported to have occurred more in government hospitals and catheterization was the commonest modes of transmission in both health facilities. CONCLUSION: the prevalence of HAIs in this state was reported to be high. Although health-care professionals have good knowledge of HAIs, active effort is not always made to identify and resolve them. Standardized surveillance of HAIs is urgently needed.

BACKGROUND:The prostate cancer prevention trial (PCPT) and Reduction by dutasteride of Prostate Cancer Events (REDUCE) trial found that 5α-reductase (5αR) inhibitors finasteride and dutasteride respectively, decreased prostate cancer prevalence but also increased the incidence of high-grade tumors. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have high 5αR1 and low 5αR2 expression. Because finasteride inhibits only 5αR2, we hypothesized that it would not be as efficacious in preventing prostate cancer development and/or progression in C57BL/6 TRAMP x FVB mice as dutasteride, which inhibits both 5αR1 and 5αR2. METHOD/PRINCIPAL FINDINGS:Six-week-old C57BL/6 TRAMP x FVB male mice were randomized to AIN93G control or pre- and post- finasteride and dutasteride diet (83.3 mg drug/kg diet) groups (n =30-33) that began at 6 and 12 weeks of age, respectively, and were terminated at 20 weeks of age. The pre- and post- finasteride and dutasteride groups were designed to test the preventive and therapeutic efficacy of the drugs, respectively. Final body weights, genitourinary tract weights, and genitourinary tract weights as percentage of body weights were significantly decreased in the Pre- and Post-dutasteride groups compared with the control. The Post-dutasteride group showed the greatest inhibition of prostatic intraepithelial neoplasia progression and prostate cancer development. Surprisingly, the Post-dutasteride group showed improved outcomes compared with the Pre-dutasteride group, which had increased incidence of high-grade carcinoma as the most common and most severe lesions in a majority of prostate lobes. Consistent with our hypothesis, we found little benefit from the finasteride diets, and they increased the incidence of high-grade carcinoma. CONCLUSION:Our findings have commonalities with previously reported PCPT, REDUCE, and the Reduction by dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial results. Our results may support the therapeutic use of dutasteride, but not finasteride, for therapeutic or preventive use.

5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) convert testosterone into the more potent androgen dihydrotestosterone. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have increased 5αR1 and decreased 5αR2 expression. Previously, finasteride (5αR2 inhibitor) treatment begun 3 weeks post-tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5αR1 expression or activity. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, whereas dutasteride (5αR1 and 5αR2 inhibitor) treatment would decrease tumor growth regardless of whether treatment was initiated before or after tumor implantation.Sixty 8-week-old male nude mice were randomized to Control, Pre- and Post-Finasteride, and Pre- and Post-Dutasteride (83.3 mg drug/kg diet) diet groups. Pre- and post-groups began their treatment diets 1-2 weeks prior to or 3 weeks after subcutaneous injection of 1×10⁵ WPE1-NA22 human prostate cancer cells, respectively. Tumors were allowed to grow for 22 weeks; tumor areas, body weights, and food intakes were measured weekly. At study's conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control; dutasteride intake significantly decreased seminal vesicle weights compared to finasteride intake. No differences were measured in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells and parent line RWPE-1 prostate epithelial cells were unaltered by treatment with testosterone, dihydrotestosterone, or mibolerone, suggesting that these cell lines are not androgen-sensitive.The lack of response of WPE1-NA22 prostate cancer cells to androgen treatment may explain the inadequate tumor growth observed. Additional studies are needed to determine whether finasteride and dutasteride are effective in decreasing prostate cancer development/growth.

Maintenance of hematopoietic stem cell (HSC) function in the niche is an orchestrated event. Osteomacs (OM) are key cellular components of the niche. Previously, we documented that osteoblasts, OM, and megakaryocytes interact to promote hematopoiesis. Here, we further characterize OM and identify megakaryocyte-induced mediators that augment the role of OM in the niche. Single-cell mRNA-seq, mass spectrometry, and CyTOF examination of megakaryocyte-stimulated OM suggested that upregulation of CD166 and Embigin on OM augment their hematopoiesis maintenance function. CD166 knockout OM or shRNA-Embigin knockdown OM confirmed that the loss of these molecules significantly reduced the ability of OM to augment the osteoblast-mediated hematopoietic-enhancing activity. Recombinant CD166 and Embigin partially substituted for OM function, characterizing both proteins as critical mediators of OM hematopoietic function. Our data identify Embigin and CD166 as OM-regulated critical components of HSC function in the niche and potential participants in various in vitro manipulations of stem cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Intracellular α-ketoglutarate is an indispensable substrate for the Jumonji family of histone demethylases (JHDMs) mediating most of the histone demethylation reactions. Since α-ketoglutarate is an intermediate of the tricarboxylic acid cycle and a product of transamination, its availability is governed by the metabolism of several amino acids. Here, we show that asparagine starvation suppresses global histone demethylation. This process is neither due to the change of expression of histone-modifying enzymes nor due to the change of intracellular levels of α-ketoglutarate. Rather, asparagine starvation reduces the intracellular pool of labile iron, a key co-factor for the JHDMs to function. Mechanistically, asparagine starvation suppresses the expression of the transferrin receptor to limit iron uptake. Furthermore, iron supplementation to the culture medium restores histone demethylation and alters gene expression to accelerate cell death upon asparagine depletion. These results suggest that suppressing iron-dependent histone demethylation is part of the cellular adaptive response to asparagine starvation., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Amino acid restriction has recently emerged as a compelling strategy to inhibit tumor growth. Recent work suggests that amino acids can regulate cellular signaling in addition to their role as biosynthetic substrates. Using lymphoid cancer cells as a model, we found that asparagine depletion acutely reduces the expression of c-MYC protein without changing its mRNA expression. Furthermore, asparagine depletion inhibits the translation of MYC mRNA without altering the rate of MYC protein degradation. Of interest, the inhibitory effect on MYC mRNA translation during asparagine depletion is not due to the activation of the general controlled nonderepressible 2 (GCN2) pathway and is not a consequence of the inhibition of global protein synthesis. In addition, both the 5' and 3' untranslated regions (UTRs) of MYC mRNA are not required for this inhibitory effect. Finally, using a MYC-driven mouse B cell lymphoma model, we found that shRNA inhibition of asparagine synthetase (ASNS) or pharmacological inhibition of asparagine production can significantly reduce the MYC protein expression and tumor growth when environmental asparagine becomes limiting. Since MYC is a critical oncogene, our results uncover a molecular connection between MYC mRNA translation and asparagine bioavailability and shed light on a potential to target MYC oncogene post-transcriptionally through asparagine restriction., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

TG-interacting factor 1 (TGIF1) is a transcriptional repressor that can modulate retinoic acid and transforming growth factor β signaling pathways. It is required for myeloid progenitor cell differentiation and survival, and mutations in the TGIF1 gene cause holoprosencephaly. Furthermore, we have previously observed that acute myelogenous leukemia (AML) patients with low TGIF1 levels had worse prognoses. Here, we explored the role of Tgif1 in murine hematopoietic stem cell (HSC) function. CFU assays showed that Tgif1(-/-) bone marrow cells produced more total colonies and had higher serial CFU potential. These effects were also observed in vivo, where Tgif1(-/-) bone marrow cells had higher repopulation potential in short- and long-term competitive repopulation assays than wild-type cells. Serial transplantation and replating studies showed that Tgif1(-/-) HSCs exhibited greater self-renewal and were less proliferative and more quiescent than wild-type cells, suggesting that Tgif1 is required for stem cells to enter the cell cycle. Furthermore, HSCs from Tgif1(+/-) mice had a phenotype similar to that of HSCs from Tgif1(-/-) mice, while bone marrow cells with overexpressing Tgif1 showed increased proliferation and lower survival in long-term transplant studies. Taken together, our data suggest that Tgif1 suppresses stem cell self-renewal and provide clues as to how reduced expression of TGIF1 may contribute to poor long-term survival in patients with AML.

ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.

The NH(2)-terminal domains of membrane-bound sterol regulatory element-binding proteins (SREBPs) are released into the cytosol by regulated intramembrane proteolysis, after which they enter the nucleus to activate genes encoding lipid biosynthetic enzymes. Intramembrane proteolysis is catalyzed by Site-2 protease (S2P), a hydrophobic zinc metalloprotease that cleaves SREBPs at a membrane-embedded leucine-cysteine bond. In the current study, we use domain-swapping methods to localize the residues within the SREBP-2 membrane-spanning segment that are required for cleavage by S2P. The studies reveal a requirement for an asparagine-proline sequence in the middle third of the transmembrane segment. We propose a model in which the asparagine-proline sequence serves as an NH(2)-terminal cap for a portion of the transmembrane alpha-helix of SREBP, allowing the remainder of the alpha-helix to unwind partially to expose the peptide bond for cleavage by S2P.