Non-Hermitian systems distinguish themselves from Hermitian systems by exhibiting a phase transition point called an exceptional point (EP), at which two eigenstates coalesce under a system parameter ...variation. Many interesting EP phenomena, such as level crossings in nuclear and condensed matter physics, and unusual phenomena in optics, such as loss-induced lasing and unidirectional transmission, can be understood by considering a simple 2×2 non-Hermitian matrix. At a higher dimension, more complex EP physics not found in two-state systems arises. We consider the emergence and interaction of multiple EPs in a four-state system theoretically and realize the system experimentally using four coupled acoustic cavities with asymmetric losses. We find that multiple EPs can emerge, and as the system parameters vary, these EPs can collide and merge, leading to higher-order singularities and topological characteristics much richer than those seen in two-state systems. The new physics obtained is not limited to the acoustic systems demonstrated here. It also applies to other systems as well, such as coupled photonic cavities and waveguides.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM, UPUK
Coating the nanoparticle surface with cancer cell recognizing ligands is expected to facilitate specific delivery of nanoparticles to diseased cells in vivo. While this targeting strategy is ...appealing, no nanoparticle-based active targeting formulation for solid tumor treatment had made it past phase III clinical trials. Here, we quantified the cancer cell-targeting efficiencies of Trastuzumab (Herceptin) and folic acid coated gold and silica nanoparticles in multiple mouse tumor models. Surprisingly, we showed that less than 14 out of 1 million (0.0014% injected dose) intravenously administrated nanoparticles were delivered to targeted cancer cells, and that only 2 out of 100 cancer cells interacted with the nanoparticles. The majority of the intratumoral nanoparticles were either trapped in the extracellular matrix or taken up by perivascular tumor associated macrophages. The low cancer cell targeting efficiency and significant uptake by noncancer cells suggest the need to re-evaluate the active targeting process and therapeutic mechanisms using quantitative methods. This will be important for developing strategies to deliver emerging therapeutics such as genome editing, nucleic acid therapy, and immunotherapy for cancer treatment using nanocarriers.
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IJS, KILJ, NUK, PNG, UL, UM
Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor ...precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes.
We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 95% CI 0.972 to 0.984; AUPRC = 0.670 95% CI 0.652 to 0.688; PPV = 0.721 95% CI 0.703 to 0.739). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 95% CI 0.838 to 0.873. Main limitations of this study included limited transportability of the model and lack of geographically independent validation.
Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mitochondrial fusion is essential for maintenance of mitochondrial function. The mitofusin GTPases control mitochondrial outer membrane fusion, whereas the dynamin-related GTPase Opa1 mediates inner ...membrane fusion. We show that mitochondrial inner membrane fusion is tuned by the level of oxidative phosphorylation (OXPHOS), whereas outer membrane fusion is insensitive. Consequently, cells from patients with pathogenic mtDNA mutations show a selective defect in mitochondrial inner membrane fusion. In elucidating the molecular mechanism of OXPHOS-stimulated fusion, we uncover that real-time proteolytic processing of Opa1 stimulates mitochondrial inner membrane fusion. OXPHOS-stimulated mitochondrial fusion operates through Yme1L, which cleaves Opa1 more efficiently under high OXPHOS conditions. Engineered cleavage of Opa1 is sufficient to mediate inner membrane fusion, regardless of respiratory state. Proteolytic cleavage therefore stimulates the membrane fusion activity of Opa1, and this feature is exploited to dynamically couple mitochondrial fusion to cellular metabolism.
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•Mitochondrial inner membrane fusion is stimulated by oxidative phosphorylation•Cleavage of Opa1 by Yme1L couples inner membrane fusion to metabolism•Opa1 cleavage stimulates mitochondrial inner membrane fusion•Diseases of mtDNA disrupt the linkage of oxidative phosphorylation to fusion
Mishra et al. show that mitochondrial inner membrane fusion is stimulated by oxidative phosphorylation, regulated by Opa1. Diseases of mtDNA disrupt the linkage of oxidative phosphorylation to fusion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exceptional points (EPs) associated with a square-root singularity have been found in many non-Hermitian systems. In most of the studies, the EPs found are isotropic, meaning that the same singular ...behavior is obtained independent of the direction from which they are approached in the parameter space. In this Letter, we demonstrate both theoretically and experimentally the existence of an anisotropic EP in an acoustic system that shows different singular behaviors when the anisotropic EP is approached from different directions in the parameter space. Such an anisotropic EP arises from the coalescence of two square-root EPs having the same chirality.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UL, UM
Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has ...unequivocally shown that psoriasis represents a bona fide T cell–mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a “feed forward” inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Studying chemosensory processing desires precise chemical cue presentation, behavioral response monitoring, and large-scale neuronal activity recording. Here we present Fish-on-Chips, a set of ...optofluidic tools for highly-controlled chemical delivery while simultaneously imaging behavioral outputs and whole-brain neuronal activities at cellular resolution in larval zebrafish. These include a fluidics-based swimming arena and an integrated microfluidics-light sheet fluorescence microscopy (µfluidics-LSFM) system, both of which utilize laminar fluid flows to achieve spatiotemporally precise chemical cue presentation. To demonstrate the strengths of the platform, we used the navigation arena to reveal binasal input-dependent behavioral strategies that larval zebrafish adopt to evade cadaverine, a death-associated odor. The µfluidics-LSFM system enables sequential presentation of odor stimuli to individual or both nasal cavities separated by only ~100 µm. This allowed us to uncover brainwide neural representations of cadaverine sensing and binasal input summation in the vertebrate model. Fish-on-Chips is readily generalizable and will empower the investigation of neural coding in the chemical senses.
The flow physics of turbulent boundary layers is investigated using spectral analysis based on the spanwise scale decomposition of the Reynolds stress transport equation, with data obtained from a ...direct numerical simulation of the turbulent boundary layer at $Re_\tau \simeq 2020$. Here, we extend the framework of Kawata & Alfredsson (Phys. Rev. Lett., vol. 120, 2018, p. 244501) for plane Couette flows to zero-pressure-gradient boundary layers. The equation contains three fundamental fluxes, which govern the Reynolds stress transport: (i) a scale flux of the interaction between small-scale and large-scale structures, and two spatial fluxes dominated by (ii) pressure and (iii) turbulent transport along the wall-normal direction. The scale flux reveals evidence of the inverse turbulent kinetic energy transfer, from small to large scales, occurring at the near-wall region, whereby for the scale flux of the Reynolds shear stress transport, the inverse transfer extends across the entire boundary layer. The wall-normal fluxes reveal the interactions occurring between scales at the buffer and logarithmic regions. In addition, there is interaction between the large-scale structures and the free stream flow occurring at the edge of the boundary layer, which was not observed in the Couette flow. Flow structures associated with inverse interscale transport of Reynolds shear stress are identified by applying conditional analysis to the spectrally decomposed velocity fields. While the inverse transport is interpreted as the net energy transfer from small-scale ejections ($Q2$) and sweeps ($Q4$) to the large-scale counterparts, conditional time estimates of the direct and inverse interscale transport reveal that both processes play a substantial role across a broad range of scales.
Objective: To study the inter-relationships between sleeping hours, working hours and obesity in subjects from a working population. Research design: A cross-sectional observation study under the ...'Better Health for Better Hong Kong' Campaign, which is a territory-wide health awareness and promotion program. Subjects: 4793 subjects (2353 (49.1%) men and 2440 (50.9%) women). Their mean age (+/-s.d.) was 42.4+/-8.9 years (range 17-83 years, median 43.0 years). Subjects were randomly selected using computer-generated codes in accordance to the distribution of occupational groups in Hong Kong. Results: The mean daily sleeping time was 7.06+/-1.03 h (women vs men: 7.14+/-1.08 h vs 6.98+/-0.96 h, P<0.001). Increasing body mass index (BMI) was associated with reducing number of sleeping hours and increasing number of working hours reaching significance in the whole group as well as among male subjects. Those with short sleeping hour (6 h or less) and long working hours (>9 h) had the highest BMI and waist in both men and women. Based on multiple regression analysis with age, smoking, alcohol drinking, systolic and diastolic blood pressure, mean daily sleeping hours and working hours as independent variables, BMI was independently associated with age, systolic and diastolic blood pressure in women, whereas waist was associated with age, smoking and blood pressure. In men, blood pressure, sleeping hours and working hours were independently associated with BMI, whereas waist was independently associated with age, smoking, blood pressure, sleeping hours and working hours in men. Conclusion: Obesity is associated with reduced sleeping hours and long working hours in men among Hong Kong Chinese working population. Further studies are needed to investigate the underlying mechanisms of this relationship and its potential implication on prevention and management of obesity.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Summary
Background
Ustekinumab, an interleukin‐12/23 inhibitor, is effective in the treatment of psoriasis. A recent Italian study showed more favourable response to ustekinumab in patients with ...positive human leucocyte antigen (HLA)‐Cw6. Nonetheless, there are differences in genetic susceptibility to psoriasis between races, and no studies have specifically assessed the candidate genetic markers in predicting therapy outcome in Chinese patients with psoriasis treated with ustekinumab.
Objectives
To determine whether HLA gene polymorphisms can predict the response to ustekinumab in Chinese patients with psoriasis.
Methods
Sixty‐six patients with psoriasis treated with ustekinumab were included in the study, and the effectiveness of ustekinumab therapy was evaluated at weeks 0, 16 and 28 by Psoriasis Area and Severity Index (PASI).
Results
More HLA‐Cw6‐positive patients achieved a PASI 75 response at week 4 compared with HLA‐Cw6‐negative patients (38% vs. 9%, P = 0·019). Similarly, at week 16, patients carrying the HLA‐Cw6 allele showed a higher likelihood of achieving PASI 50, 75 and 90 than Cw6‐negative patients, although this was not statistically significant. At week 28, a significantly higher percentage of HLA‐Cw6‐positive patients maintained PASI 90 response compared with Cw6‐negative patients (63% vs. 26%, P = 0·035). Further analysis of other HLA allele polymorphisms did not show significant associations with therapeutic response to ustekinumab.
Conclusions
This pharmacogenetic study provides preliminary data indicating that positive HLA‐Cw6 is associated with a good response to ustekinumab treatment in Chinese patients with psoriasis.
What's already known about this topic?
Biological therapies have revolutionized the treatment of psoriasis. Variability in genes involved in the immunological pathways of biological therapy may account for the different treatment outcomes.
Human leucocyte antigen (HLA)‐Cw6 is the major psoriasis susceptibility gene and has a strong association with clinical psoriasis phenotypes.
Studies investigating potential predictors for response to biologics are limited, particularly in Asian populations.
What does this study add?
Our study showed that HLA‐Cw6‐positive patients have a faster response and maintain a longer treatment response to ustekinumab than HLA‐Cw6‐negative patients.
HLA‐Cw6 can be a pragmatic predictor for the response to ustekinumab not only in white patients but also in Chinese patients with psoriasis.
These results will help dermatologists in guiding therapeutic decisions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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