Cancer immunotherapy has revolutionized cancer treatment, and it relies heavily on the comprehensive understanding of the immune landscape of the tumor microenvironment (TME). Here, we obtain a detailed immune cell atlas of esophageal squamous cell carcinoma (ESCC) at single-cell resolution. Exhausted T and NK cells, regulatory T cells (Tregs), alternatively activated macrophages and tolerogenic dendritic cells are dominant in the TME. Transcriptional profiling coupled with T cell receptor (TCR) sequencing reveal lineage connections in T cell populations. CD8 T cells show continuous progression from pre-exhausted to exhausted T cells. While exhausted CD4, CD8 T and NK cells are major proliferative cell components in the TME, the crosstalk between macrophages and Tregs contributes to potential immunosuppression in the TME. Our results indicate several immunosuppressive mechanisms that may be simultaneously responsible for the failure of immuno-surveillance. Specific targeting of these immunosuppressive pathways may reactivate anti-tumor immune responses in ESCC.
Stretchable physical sensors that can detect and quantify human physiological signals such as temperature, are essential to the realization of healthcare devices for biomedical monitoring and human-machine interfaces. Despite recent achievements in stretchable electronic sensors using various conductive materials and structures, the design of stretchable sensors in optics remains a considerable challenge. Here, an optical strategy for the design of stretchable temperature sensors, which can maintain stable performance even under a strain deformation up to 80%, is reported. The optical temperature sensor is fabricated by the incorporation of thermal-sensitive upconversion nanoparticles (UCNPs) in stretchable polymer-based optical fibers (SPOFs). The SPOFs are made from stretchable elastomers and constructed in a step-index core/cladding structure for effective light confinements. The UCNPs, incorporated in the SPOFs, provide thermal-sensitive upconversion emissions at dual wavelengths for ratiometric temperature sensing by near-infrared excitation, while the SPOFs endow the sensor with skin-like mechanical compliance and excellent light-guiding characteristics for laser delivery and emission collection. The broad applications of the proposed sensor in real-time monitoring of the temperature and thermal activities of the human body, providing optical alternatives for wearable health monitoring, are demonstrated.
Flexible and stretchable strain sensors are essential to developing smart wearable devices for monitoring human activities. Such sensors have been extensively exploited with various conductive materials and structures, which, however, are normally in need of complex manufacturing processes and confronted with the challenge to achieve both large stretchability and high sensitivity. Here, we report a simple and low-cost optical strategy for the design of stretchable strain sensors which are capable of measuring large strains of 100% with a low detection limit (±0.09%), a fast responsivity (<12 ms), and high reproducibility (over 6000 cycles). The optical strain sensor (OS2) is fabricated by assembling plasmonic gold nanoparticles (GNPs) in stretchable elastomer-based optical fibers, where a core/cladding structure with step-index configuration is adopted for light confinement. The stretchable, GNP-incorporated optical fiber shows strong localized surface plasmon resonance effects that enable sensitive and reversible detection of strain deformations with high linearity and negligible hysteresis. The unique mechanical and sensing properties of the OS2 enable its assembling into clothing or mounting on skin surfaces for monitoring various human activities from physiological signals as subtle as wrist pulses to large motions of joint bending and hand gestures. We further apply the OS2 for quantitative analysis of motor disorders such as Parkinson’s disease and demonstrate its compatibility in strong electromagnetic interference environments during functional magnetic resonance imaging, showing great promises for diagnostics and assessments of motor neuron diseases in clinics.
Wearable and skin‐mountable strain sensors are highly demanding for monitoring skin deformations induced by human activities. Realization of such sensor devices based on fiber‐optic approaches offers attractive advantages such as electromagnetic immunity and inherent electric safety in comparison to their electronic counterparts. However, fiber‐optic sensors, conventionally made of stiff silica fibers, are not mechanically compliant with the soft human skins and have limited strain range (<1%) for measuring large deformations. Here, a stretchable fiber Bragg grating (FBG)‐based optical (SFO) strain sensor with skin‐like compliance for human activity monitoring is presented. The SFO sensor is fabricated by a sinuous‐shaped FBG incorporated with a stretchable substrate that responds to strain deformations by shifting of the Bragg wavelength. This structural design enables measurement of various dynamic strains associated with tension, bending and torsion in a large sensing range up to 50%. To facilitate wearable integrations, a novel free‐running fiber laser with coherent dual‐comb output is developed to interrogate the SFO sensors by dual‐comb spectroscopy, which enables fast spectral acquisition with a single photodiode. It is shown that the SFO strain sensors can be used for wearable and skin‐mountable detection of diverse human activities including breathing, phonation, facial expression, and joint movements in real time.
Depression associated with structural brain abnormalities is hypothesized to be related with accelerated brain aging. However, there is far from a unified conclusion because of clinical variations such as medication status, cumulative illness burden. To explore whether brain age is accelerated in never-treated first-episode patients with depression and its association with clinical characteristics, we constructed a prediction model where gray matter volumes measured by voxel-based morphometry derived from T1-weighted MRI scans were treated as features. The prediction model was first validated using healthy controls (HCs) in two Chinese Han datasets (Dataset 1, N = 130 for HCs and N = 195 for patients with depression; Dataset 2, N = 270 for HCs) separately or jointly, then the trained prediction model using HCs (N = 400) was applied to never-treated first-episode patients with depression (N = 195). The brain-predicted age difference (brain-PAD) scores defined as the difference between predicted brain age and chronological age, were calculated for all participants and compared between patients with age-, gender-, educational level-matched HCs in Dataset 1. Overall, patients presented higher brain-PAD scores suggesting patients Shaoqiang Han and Yuan Chen contributed equally to this study.
Early life events can lead to multiple diseases in adulthood. Previous studies suggested that polysorbate 80 (P80) as a widely used emulsifier in pharmaceutical formulations and food industries could impair the intestinal barrier. However, whether maternal P80 (MP80) exposure could affect the long-term health of offspring remains unknown. In this study, we found that maternal P80 intake could retard intestinal development, disrupt the intestinal barrier, and cause low-grade intestinal inflammation in 3-week-old offspring. 16S rRNA sequencing and correlation analysis revealed that Mucispirillum, Clostridium XI, and Parabacteroides, which positively correlated with intestinal proliferation and differentiation, were decreased in the maternal P80 group. Interestingly, the increase in some harmful bacteria, including Proteobacteria, Helicobacteraceae, Campylobacterales, and Desulfovibrionales, persisted from the weaning period to adulthood (3 to 8 weeks). Furthermore, a fecal microbiota transplantation assay showed that the mice gavaged with feces from 3-week-old offspring of the MP80 group presented more severe intestinal inflammation and barrier disruption than the mice that received feces from the offspring of the control group. Finally, maternal P80 intake remarkably aggravated the structural disorder of intestinal crypt, increased proinflammatory factors, and exacerbated dextran sulfate sodium (DSS)-induced colitis in adulthood. Conclusively, maternal P80 intake could induce gut dysbiosis and promote colitis susceptibility in adulthood. This study provides new insights into the prevention of inflammatory bowel disease (IBD). IMPORTANCE The main findings of this research showed that maternal P80 intake could disrupt the intestinal barrier, induce gut dysbiosis, and promote colitis susceptibility in adulthood. This study will enhance understanding of the prevention of IBD.
Background: Major depressive disorder (MDD) has demonstrated abnormalities of static intrinsic brain activity measured by amplitude of low-frequency fluctuation (ALFF). Recent studies regarding the resting-state functional magnetic resonance imaging (rs-fMRI) have found the brain activity is inherently dynamic over time. Little is known, however, regarding the temporal dynamics of local neural activity in MDD. Here, we investigated whether temporal dynamic changes in spontaneous neural activity are influenced by MDD.Methods: We recruited 81 first-episode, drug-naive MDD patients and 64 age-, gender-, and education-matched healthy controls who underwent rs-fMRI. A sliding-window approach was then adopted for the estimation of dynamic ALFF (dALFF), which was used to measure time-varying brain activity and then compared between the two groups. The relationship between altered dALFF variability and clinical variables in MDD patients was also analyzed.Results: MDD patients showed increased temporal variability (dALFF) mainly focused on the bilateral thalamus, the bilateral superior frontal gyrus, the right middle frontal gyrus, the bilateral cerebellum posterior lobe, and the vermis. Furthermore, increased dALFF variability values in the right thalamus and right cerebellum posterior lobe were positively correlated with MDD symptom severity.Conclusions: The overall results suggest that altered temporal variability in corticocerebellar–thalamic–cortical circuit (CCTCC), involved in emotional, executive, and cognitive, is associated with drug-naive, first-episode MDD patients. Moreover, our study highlights the vital role of abnormal dynamic brain activity in the cerebellar hemisphere associated with CCTCC in MDD patients. These findings may provide novel insights into the pathophysiological mechanisms of MDD.
Glucose monitoring sensors with high softness and flexibility are critical for the developments of wearable and implantable healthcare devices that enable diagnosis, prognosis, and management of diabetes. The design and implementation of such sensors have been extensively exploited by electrochemical strategies, which, however, suffer from poor reusability and complex modification procedures, and necessitate frequent calibration or sensor replacement due to enzymatic reaction instability. Here, a soft and plasmonic hydrogel optical sensor is created for quantitative and continuous glucose monitoring under physiological conditions. The optical sensor consists of a flexible optical fiber made from composites of gold nanoparticles and glucose-responsive hydrogels. The reversible binding of glucose to the nanocomposite optical fiber results in dynamic volume expansion of the hydrogel matrix, which modulates the localized surface plasmon resonance effect, enabling glucose to be quantified from the light transmission. To achieve robust readout, a dual-wavelength differential approach is employed to endow the sensor with self calibration capability. We show that the sensor is reversible and reusable for detecting physiological glucose levels with high linearity and negligible hysteresis. The soft and flexible glucose sensor holds great promises of serving as a minimally-invasive probe for point-of-care glucose monitoring in clinics.
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