Inverse design of mid-infrared diamond waveguide beam splitter.

Diamond is a supreme material for mid-infrared (MIR) integrated photonics as it has a transparency window up to 20 µm that covers the entire fingerprint region. However, its relatively low refractive index poses a challenge in designing an MIR diamond functional device with both small footprint and high transmission efficiency. Here we propose and demonstrate the inverse design of an MIR diamond waveguide beam splitter operating at the wavelength of 15 µm with a small footprint of ∼15 µm × âˆ¼15 µm and a total transmission efficiency above 95%. Our work paves a new avenue for the design of compact and high-efficiency MIR diamond photonic devices.

An unusual case of traumatic injury to the first metatarsal a case report.

A 44-year-old male sustained trauma to his foot leading to a 5-cm defect of the first metatarsal bone and infection of the bone by Staphylococcus aureus. Osteotomy is the most suitable method for treating large metatarsal defects complicated with osteomyelitis, however few reports have been published on this challenging approach. In this case, osteotomy and external fixation for distraction were performed. Finally, the osteomyelitis of the patient was well controlled, the bone length was restored, and the patient could carry weight completely, and the treatment effect was satisfactory.

Manipulation of photosynthetic energy transfer by vibrational strong coupling.

Uncovering the mystery of efficient and directional energy transfer in photosynthetic organisms remains a critical challenge in quantum biology. Recent experimental evidence and quantum theory developments indicate the significance of quantum features of molecular vibrations in assisting photosynthetic energy transfer, which provides the possibility of manipulating the process by controlling molecular vibrations. Here, we propose and theoretically demonstrate efficient manipulation of photosynthetic energy transfer by using vibrational strong coupling between the vibrational state of a Fenna-Matthews-Olson (FMO) complex and the vacuum state of an optical cavity. Specifically, based on a full-quantum analytical model to describe the strong coupling effect between the optical cavity and molecular vibration, we realize efficient manipulation of energy transfer efficiency (from 58% to 92%) and energy transfer time (from 20 to 500 ps) in one branch of FMO complex by actively controlling the coupling strength and the quality factor of the optical cavity under both near-resonant and off-resonant conditions, respectively. Our work provides a practical scenario to manipulate photosynthetic energy transfer by externally interfering molecular vibrations via an optical cavity and a comprehensible conceptual framework for researching other similar systems.

Deciphering the Potential of Multidimensional Carbon Materials for Surface-Enhanced Raman Spectroscopy through Density Functional Theory.

Surface-enhanced Raman spectroscopy (SERS) is a potent analytical tool, particularly for molecular identification and structural analysis. Conventional metallic SERS substrates, however, suffer from low reproducibility and compatibility with biological molecules. Recently, metal-free SERS substrates based on chemical enhancement have emerged as a promising alternative with carbon-based materials offering excellent reproducibility and compatibility. Nevertheless, our understanding of carbon materials in SERS remains limited, which hinders their rational design. Here we systematically explore multidimensional carbon materials, including zero-dimensional fullerenes (C60), one-dimensional carbon nanotubes, two-dimensional graphene, and their B-, N-, and O-doped derivatives, for SERS applications. Using density functional theory, we elucidate the nonresonant polarizability-enhanced and resonant charge-transfer-based chemical enhancement mechanisms of these materials by evaluating their static/dynamic polarizability and electron excitation properties. This work provides a critical reference for the future design of carbon-based SERS substrates, opening a new avenue in this field.

Unlocking the secrets of the invisible world: incredible deep optical imaging through in-silico clearing.

In-silico clearing enables deep optical imaging of biological samples by correcting image blur caused by scattering and aberration. This breakthrough method offers researchers unprecedented insights into three-dimensional biological systems, with enormous potential for advancing biology and medicine to better understand living organisms and human health.

Ultracompact Vernier-effect-improved sensor by a single microfiber-knot resonator.

Fiber-optic sensors are an indispensable element of modern sensing technologies by virtue of their low cost, excellent electromagnetic immunity, and remote sensing capability. Optical Vernier effect is widely used to enhance sensitivity of fiber-optic sensors but requires bulky and complex cascaded interferometers. Here we propose and experimentally demonstrate an ultracompact (∼2 mm by ∼2 mm) Vernier-effect-improved sensor by only using a single microfiber-knot resonator. With the Vernier effect achieved by controlling the optical beating with the spectral ripple of a super light emitting diode (SLED), we show ∼20x sensitivity enhancement for quantitative temperature monitoring. Our sensor creates a new practical method to realize Vernier effect in fiber-optic sensors and beyond.

Typing of acute leukemia by intelligent optical time-stretch imaging flow cytometry on a chip.

Acute leukemia (AL) is one of the top life-threatening diseases. Accurate typing of AL can significantly improve its prognosis. However, conventional methods for AL typing often require cell staining, which is time-consuming and labor-intensive. Furthermore, their performance is highly limited by the specificity and availability of fluorescent labels, which can hardly meet the requirements of AL typing in clinical settings. Here, we demonstrate AL typing by intelligent optical time-stretch (OTS) imaging flow cytometry on a microfluidic chip. Specifically, we employ OTS microscopy to capture the images of cells in clinical bone marrow samples with a spatial resolution of 780 nm at a high flowing speed of 1 m s-1 in a label-free manner. Then, to show the clinical utility of our method for which the features of clinical samples are diverse, we design and construct a deep convolutional neural network (CNN) to analyze the cellular images and determine the AL type of each sample. We measure 30 clinical samples composed of 7 acute lymphoblastic leukemia (ALL) samples, 17 acute myelogenous leukemia (AML) samples, and 6 samples from healthy donors, resulting in a total of 227 620 images acquired. Results show that our method can distinguish ALL and AML with an accuracy of 95.03%, which, to the best of our knowledge, is a record in label-free AL typing. In addition to AL typing, we believe that the high throughput, high accuracy, and label-free operation of our method make it a potential solution for cell analysis in scientific research and clinical settings.

Place & Play SERS: sample collection and preparation-free surface-enhanced Raman spectroscopy.

The ability to perform sensitive, real-time, in situ, multiplex chemical analysis is indispensable for diverse applications such as human health monitoring, food safety testing, forensic analysis, environmental sensing, and homeland security. Surface-enhanced Raman spectroscopy (SERS) is an effective tool to offer the ability by virtue of its high sensitivity and rapid label-free signal detection as well as the availability of portable Raman spectrometers. Unfortunately, the practical utility of SERS is limited because it generally requires sample collection and preparation, namely, collecting a sample from an object of interest and placing the sample on top of a SERS substrate to perform a SERS measurement. In fact, not all analytes can satisfy this requirement because the sample collection and preparation process may be undesirable, laborious, difficult, dangerous, costly, or time-consuming. Here we introduce "Place & Play SERS" based on an ultrathin, flexible, stretchable, adhesive, biointegratable gold-deposited polyvinyl alcohol (PVA) nanomesh substrate that enables placing the substrate on top of an object of interest and performing a SERS measurement of the object by epi-excitation without the need for touching, destroying, and sampling it. Specifically, we characterized the sensitivity of the gold/PVA nanomesh substrate in the Place & Play SERS measurement scheme and then used the scheme to conduct SERS measurements of both wet and dry objects under nearly real-world conditions. To show the practical utility of Place & Play SERS, we demonstrated two examples of its application: food safety testing and forensic analysis. Our results firmly verified the new measurement scheme of SERS and are expected to extend the potential of SERS by opening up untapped applications of sensitive, real-time, in situ multiplex chemical analysis.

Real-time intelligent classification of COVID-19 and thrombosis via massive image-based analysis of platelet aggregates.

Microvascular thrombosis is a typical symptom of COVID-19 and shows similarities to thrombosis. Using a microfluidic imaging flow cytometer, we measured the blood of 181 COVID-19 samples and 101 non-COVID-19 thrombosis samples, resulting in a total of 6.3 million bright-field images. We trained a convolutional neural network to distinguish single platelets, platelet aggregates, and white blood cells and performed classical image analysis for each subpopulation individually. Based on derived single-cell features for each population, we trained machine learning models for classification between COVID-19 and non-COVID-19 thrombosis, resulting in a patient testing accuracy of 75%. This result indicates that platelet formation differs between COVID-19 and non-COVID-19 thrombosis. All analysis steps were optimized for efficiency and implemented in an easy-to-use plugin for the image viewer napari, allowing the entire analysis to be performed within seconds on mid-range computers, which could be used for real-time diagnosis.

Studying the efficacy of antiplatelet drugs on atherosclerosis by optofluidic imaging on a chip.

Vascular stenosis caused by atherosclerosis instigates activation and aggregation of platelets, eventually resulting in thrombus formation. Although antiplatelet drugs are commonly used to inhibit platelet activation and aggregation, they unfortunately cannot prevent recurrent thrombotic events in patients with atherosclerosis. This is partially due to the limited understanding of the efficacy of antiplatelet drugs in the complex hemodynamic environment of vascular stenosis. Conventional methods for evaluating the efficacy of antiplatelet drugs under stenosis either fail to simulate the hemodynamic environment of vascular stenosis characterized by high shear stress and recirculatory flow or lack spatial resolution in their analytical techniques to statistically identify and characterize platelet aggregates. Here we propose and experimentally demonstrate a method comprising an in vitro 3D stenosis microfluidic chip and an optical time-stretch quantitative phase imaging system for studying the efficacy of antiplatelet drugs under stenosis. Our method simulates the atherogenic flow environment of vascular stenosis while enabling high-resolution and statistical analysis of platelet aggregates. Using our method, we distinguished the efficacy of three antiplatelet drugs, acetylsalicylic acid (ASA), cangrelor, and eptifibatide, for inhibiting platelet aggregation induced by stenosis. Specifically, ASA failed to inhibit stenosis-induced platelet aggregation, while eptifibatide and cangrelor showed high and moderate efficacy, respectively. Furthermore, we demonstrated that the drugs tested also differed in their efficacy for inhibiting platelet aggregation synergistically induced by stenosis and agonists (e.g., adenosine diphosphate, and collagen). Taken together, our method is an effective tool for investigating the efficacy of antiplatelet drugs under vascular stenosis, which could assist the development of optimal pharmacologic strategies for patients with atherosclerosis.

Long-term effects of Pfizer-BioNTech COVID-19 vaccinations on platelets.

There is a global concern about the safety of COVID-19 vaccines associated with platelet function. However, their long-term effects on overall platelet activity remain poorly understood. Here we address this problem by image-based single-cell profiling and temporal monitoring of circulating platelet aggregates in the blood of healthy human subjects, before and after they received multiple Pfizer-BioNTech (BNT162b2) vaccine doses over a time span of nearly 1 year. Results show no significant or persisting platelet aggregation trends following the vaccine doses, indicating that any effects of vaccinations on platelet turnover, platelet activation, platelet aggregation, and platelet-leukocyte interaction was insignificant.

Graphene oxide bulk material reinforced by heterophase platelets with multiscale interface crosslinking.

Graphene oxide (GO) and reduced GO possess robust mechanical, electrical and chemical properties. Their nanocomposites have been extensively explored for applications in diverse fields. However, due to the high flexibility and weak interlayer interactions of GO nanosheets, the flexural mechanical properties of GO-based composites, especially in bulk materials, are largely constrained, which hinders their performance in practical applications. Here, inspired by the amorphous/crystalline feature of the heterophase within nacreous platelets, we present a centimetre-sized, GO-based bulk material consisting of building blocks of GO and amorphous/crystalline leaf-like MnO2 hexagon nanosheets adhered together with polymer-based crosslinkers. These building blocks are stacked and hot-pressed with further crosslinking between the layers to form a GO/MnO2-based layered (GML) bulk material. The resultant GML bulk material exhibits a flexural strength of 231.2 MPa. Moreover, the material exhibits sufficient fracture toughness and strong impact resistance while being light in weight. Experimental and numerical analyses indicate that the ordered heterophase structure and synergetic crosslinking interactions across multiscale interfaces lead to the superior mechanical properties of the material. These results are expected to provide insights into the design of structural materials and potential applications of high-performance GO-based bulk materials in aerospace, biomedicine and electronics.

ZnT8 loss-of-function accelerates functional maturation of hESC-derived ß cells and resists metabolic stress in diabetes.

Human embryonic stem cell-derived ß cells (SC-ß cells) hold great promise for treatment of diabetes, yet how to achieve functional maturation and protect them against metabolic stresses such as glucotoxicity and lipotoxicity remains elusive. Our single-cell RNA-seq analysis reveals that ZnT8 loss of function (LOF) accelerates the functional maturation of SC-ß cells. As a result, ZnT8 LOF improves glucose-stimulated insulin secretion (GSIS) by releasing the negative feedback of zinc inhibition on insulin secretion. Furthermore, we demonstrate that ZnT8 LOF mutations endow SC-ß cells with resistance to lipotoxicity/glucotoxicity-triggered cell death by alleviating endoplasmic reticulum (ER) stress through modulation of zinc levels. Importantly, transplantation of SC-ß cells with ZnT8 LOF into mice with preexisting diabetes significantly improves glycemia restoration and glucose tolerance. These findings highlight the beneficial effect of ZnT8 LOF on the functional maturation and survival of SC-ß cells that are useful as a potential source for cell replacement therapies.

Massive image-based single-cell profiling reveals high levels of circulating platelet aggregates in patients with COVID-19.

A characteristic clinical feature of COVID-19 is the frequent incidence of microvascular thrombosis. In fact, COVID-19 autopsy reports have shown widespread thrombotic microangiopathy characterized by extensive diffuse microthrombi within peripheral capillaries and arterioles in lungs, hearts, and other organs, resulting in multiorgan failure. However, the underlying process of COVID-19-associated microvascular thrombosis remains elusive due to the lack of tools to statistically examine platelet aggregation (i.e., the initiation of microthrombus formation) in detail. Here we report the landscape of circulating platelet aggregates in COVID-19 obtained by massive single-cell image-based profiling and temporal monitoring of the blood of COVID-19 patients (n = 110). Surprisingly, our analysis of the big image data shows the anomalous presence of excessive platelet aggregates in nearly 90% of all COVID-19 patients. Furthermore, results indicate strong links between the concentration of platelet aggregates and the severity, mortality, respiratory condition, and vascular endothelial dysfunction level of COVID-19 patients.

Synthetic hydrogel nanoparticles for sepsis therapy.

Sepsis is a life-threatening condition caused by the extreme release of inflammatory mediators into the blood in response to infection (e.g., bacterial infection, COVID-19), resulting in the dysfunction of multiple organs. Currently, there is no direct treatment for sepsis. Here we report an abiotic hydrogel nanoparticle (HNP) as a potential therapeutic agent for late-stage sepsis. The HNP captures and neutralizes all variants of histones, a major inflammatory mediator released during sepsis. The highly optimized HNP has high capacity and long-term circulation capability for the selective sequestration and neutralization of histones. Intravenous injection of the HNP protects mice against a lethal dose of histones through the inhibition of platelet aggregation and migration into the lungs. In vivo administration in murine sepsis model mice results in near complete survival. These results establish the potential for synthetic, nonbiological polymer hydrogel sequestrants as a new intervention strategy for sepsis therapy and adds to our understanding of the importance of histones to this condition.

Single-cell RNA Sequencing Reveals Sexually Dimorphic Transcriptome and Type 2 Diabetes Genes in Mouse Islet ß Cells.

Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic ß cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse ß cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of ß cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.

All-dielectric chiral-field-enhanced Raman optical activity.

Raman optical activity (ROA) is effective for studying the conformational structure and behavior of chiral molecules in aqueous solutions and is advantageous over X-ray crystallography and nuclear magnetic resonance spectroscopy in sample preparation and cost performance. However, ROA signals are inherently minuscule; 3-5 orders of magnitude weaker than spontaneous Raman scattering due to the weak chiral light-matter interaction. Localized surface plasmon resonance on metallic nanoparticles has been employed to enhance ROA signals, but suffers from detrimental spectral artifacts due to its photothermal heat generation and inability to efficiently transfer and enhance optical chirality from the far field to the near field. Here we demonstrate all-dielectric chiral-field-enhanced ROA by devising a silicon nanodisk array and exploiting its dark mode to overcome these limitations. Specifically, we use it with pairs of chemical and biological enantiomers to show >100x enhanced chiral light-molecule interaction with negligible artifacts for ROA measurements.

Intelligent Platelet Morphometry.

Technological advances in image-based platelet analysis or platelet morphometry are critical for a better understanding of the structure and function of platelets in biological research as well as for the development of better clinical strategies in medical practice. Recently, the advent of high-throughput optical imaging and deep learning has boosted platelet morphometry to the next level by providing a new set of capabilities beyond what is achievable with traditional platelet morphometry, shedding light on the unexplored domain of platelet analysis. This Opinion article introduces emerging opportunities in 'intelligent' platelet morphometry, which are expected to pave the way for a new class of diagnostics, pharmacometrics, and therapeutics.

LncRNA TUG1 promotes the intervertebral disc degeneration and nucleus pulposus cell apoptosis though modulating miR-26a/HMGB1 axis and regulating NF-κB activation.

AIMS: This study was to investigate the effect of TUG1 on apoptosis and ECM degradation of human degenerative intervertebral disc nucleus pulposus cells (NPCs) and its mechanism. METHODS: Human degenerative intervertebral disc NP tissues were obtained from 10 patients with lumbar disc herniation (LDH) who underwent lumbar spine surgery (IDD group), normal intervertebral disc NP tissues were obtained from 10 patients with lumbar vertebrae fractures (LVF group). RESULTS: The expression of TUG1 and HMGB1 protein in human degenerative disc NP tissues and NPCs was significantly increased, while the level of miR-26a was significantly decreased. Overexpression of TUG1 inhibited the proliferation while promoted apoptosis and ECM degradation of human degenerative intervertebral disc NPCs. Simultaneously, the effect of TUG1 knockdown on NPCs was opposite. Interestingly, TUG1 acted as an endogenous sponge to down-regulate the expression of miR-26a in NPCs by direct binding to miR-26a. Overexpression of miR-26a reversed the effects of TUG1 overexpression on apoptosis and ECM degradation. Additionally, HMGB1 was a target gene of miR-26a. The increased expression of HMGB1 induced by TUG1 overexpression could be reversed by the introduction of miR-26a mimic. Overexpression of TUG1 significantly upregulated the expression of p65 in the nucleus, while overexpression of TUG1 partially abolished the inhibition of NF-κB by QNZ pretreatment. CONCLUSION: TUG1 could promote the apoptosis and ECM degradation of degenerated intervertebral disc NPCs by regulating the miR-26a/HMGB1, which may be involved in the activation of NF-κB pathway.

Porous carbon nanowire array for surface-enhanced Raman spectroscopy.

Surface-enhanced Raman spectroscopy (SERS) is a powerful tool for vibrational spectroscopy as it provides several orders of magnitude higher sensitivity than inherently weak spontaneous Raman scattering by exciting localized surface plasmon resonance (LSPR) on metal substrates. However, SERS can be unreliable for biomedical use since it sacrifices reproducibility, uniformity, biocompatibility, and durability due to its strong dependence on "hot spots", large photothermal heat generation, and easy oxidization. Here, we demonstrate the design, fabrication, and use of a metal-free (i.e., LSPR-free), topologically tailored nanostructure composed of porous carbon nanowires in an array as a SERS substrate to overcome all these problems. Specifically, it offers not only high signal enhancement (~106) due to its strong broadband charge-transfer resonance, but also extraordinarily high reproducibility due to the absence of hot spots, high durability due to no oxidization, and high compatibility to biomolecules due to its fluorescence quenching capability.