Mammalian Near-Infrared Image Vision through Injectable and Self-Powered Retinal Nanoantennae.

Mammals cannot see light over 700 nm in wavelength. This limitation is due to the physical thermodynamic properties of the photon-detecting opsins. However, the detection of naturally invisible near-infrared (NIR) light is a desirable ability. To break this limitation, we developed ocular injectable photoreceptor-binding upconversion nanoparticles (pbUCNPs). These nanoparticles anchored on retinal photoreceptors as miniature NIR light transducers to create NIR light image vision with negligible side effects. Based on single-photoreceptor recordings, electroretinograms, cortical recordings, and visual behavioral tests, we demonstrated that mice with these nanoantennae could not only perceive NIR light, but also see NIR light patterns. Excitingly, the injected mice were also able to differentiate sophisticated NIR shape patterns. Moreover, the NIR light pattern vision was ambient-daylight compatible and existed in parallel with native daylight vision. This new method will provide unmatched opportunities for a wide variety of emerging bio-integrated nanodevice designs and applications. VIDEO ABSTRACT.

Electric Fields and Enzyme Catalysis.

What happens inside an enzyme's active site to allow slow and difficult chemical reactions to occur so rapidly? This question has occupied biochemists' attention for a long time. Computer models of increasing sophistication have predicted an important role for electrostatic interactions in enzymatic reactions, yet this hypothesis has proved vexingly difficult to test experimentally. Recent experiments utilizing the vibrational Stark effect make it possible to measure the electric field a substrate molecule experiences when bound inside its enzyme's active site. These experiments have provided compelling evidence supporting a major electrostatic contribution to enzymatic catalysis. Here, we review these results and develop a simple model for electrostatic catalysis that enables us to incorporate disparate concepts introduced by many investigators to describe how enzymes work into a more unified framework stressing the importance of electric fields at the active site.

Near-infrared nanosensors enable optical imaging of oxytocin with selectivity over vasopressin in acute mouse brain slices.

Oxytocin plays a critical role in regulating social behaviors, yet our understanding of its function in both neurological health and disease remains incomplete. Real-time oxytocin imaging probes with spatiotemporal resolution relevant to its endogenous signaling are required to fully elucidate oxytocin's role in the brain. Herein, we describe a near-infrared oxytocin nanosensor (nIROXT), a synthetic probe capable of imaging oxytocin in the brain without interference from its structural analogue, vasopressin. nIROXT leverages the inherent tissue-transparent fluorescence of single-walled carbon nanotubes (SWCNT) and the molecular recognition capacity of an oxytocin receptor peptide fragment to selectively and reversibly image oxytocin. We employ these nanosensors to monitor electrically stimulated oxytocin release in brain tissue, revealing oxytocin release sites with a median size of 3 µm in the paraventricular nucleus of C57BL/6 mice, which putatively represents the spatial diffusion of oxytocin from its point of release. These data demonstrate that covalent SWCNT constructs, such as nIROXT, are powerful optical tools that can be leveraged to measure neuropeptide release in brain tissue.

A billion years of evolution manifest in nanosecond protein dynamics.

Protein dynamics form a critical bridge between protein structure and function, yet the impact of evolution on ultrafast processes inside proteins remains enigmatic. This study delves deep into nanosecond-scale protein dynamics of a structurally and functionally conserved protein across species separated by almost a billion years, investigating ten homologs in complex with their ligand. By inducing a photo-triggered destabilization of the ligand inside the binding pocket, we resolved distinct kinetic footprints for each homolog via transient infrared spectroscopy. Strikingly, we found a cascade of rearrangements within the protein complex which manifest in time points of increased dynamic activity conserved over hundreds of millions of years within a narrow window. Among these processes, one displays a subtle temporal shift correlating with evolutionary divergence, suggesting reduced selective pressure in the past. Our study not only uncovers the impact of evolution on molecular processes in a specific case, but has also the potential to initiate a field of scientific inquiry within molecular paleontology, where species are compared and classified based on the rapid pace of protein dynamic processes; a field which connects the shortest conceivable time scale in living matter (10[Formula: see text] s) with the largest ones (10[Formula: see text] s).

Control of tissue oxygenation by S-nitrosohemoglobin in human subjects.

S-Nitrosohemoglobin (SNO-Hb) is unique among vasodilators in coupling blood flow to tissue oxygen requirements, thus fulfilling an essential function of the microcirculation. However, this essential physiology has not been tested clinically. Reactive hyperemia following limb ischemia/occlusion is a standard clinical test of microcirculatory function, which has been ascribed to endothelial nitric oxide (NO). However, endothelial NO does not control blood flow governing tissue oxygenation, presenting a major quandary. Here we show in mice and humans that reactive hyperemic responses (i.e., reoxygenation rates following brief ischemia/occlusion) are in fact dependent on SNO-Hb. First, mice deficient in SNO-Hb (i.e., carrying C93A mutant Hb refractory to S-nitrosylation) showed blunted muscle reoxygenation rates and persistent limb ischemia during reactive hyperemia testing. Second, in a diverse group of humans-including healthy subjects and patients with various microcirculatory disorders-strong correlations were found between limb reoxygenation rates following occlusion and both arterial SNO-Hb levels (n = 25; P = 0.042) and SNO-Hb/total HbNO ratios (n = 25; P = 0.009). Secondary analyses showed that patients with peripheral artery disease had significantly reduced SNO-Hb levels and blunted limb reoxygenation rates compared with healthy controls (n = 8 to 11/group; P < 0.05). Low SNO-Hb levels were also observed in sickle cell disease, where occlusive hyperemic testing was deemed contraindicated. Altogether, our findings provide both genetic and clinical support for the role of red blood cells in a standard test of microvascular function. Our results also suggest that SNO-Hb is a biomarker and mediator of blood flow governing tissue oxygenation. Thus, increases in SNO-Hb may improve tissue oxygenation in patients with microcirculatory disorders.

The hypothermic nature of fungi.

Fungi play essential roles in global health, ecology, and economy, but their thermal biology is relatively unexplored. Mushrooms, the fruiting body of mycelium, were previously noticed to be colder than surrounding air through evaporative cooling. Here, we confirm those observations using infrared thermography and report that this hypothermic state is also observed in mold and yeast colonies. The relatively colder temperature of yeasts and molds is also mediated via evaporative cooling and associated with the accumulation of condensed water droplets on plate lids above colonies. The colonies appear coldest at their center and the surrounding agar appears warmest near the colony edges. The analysis of cultivated Pleurotus ostreatus mushrooms revealed that the hypothermic feature of mushrooms can be observed throughout the whole fruiting process and at the level of mycelium. The mushroom's hymenium was coldest, and different areas of the mushroom appear to dissipate heat differently. We also constructed a mushroom-based air-cooling prototype system capable of passively reducing the temperature of a semiclosed compartment by approximately 10 °C in 25 min. These findings suggest that the fungal kingdom is characteristically cold. Since fungi make up approximately 2% of Earth's biomass, their evapotranspiration may contribute to cooler temperatures in local environments.

Design and synthesis of a small molecular NIR-II chemiluminescence probe for in vivo-activated H2S imaging.

Chemiluminescence (CL) with the elimination of excitation light and minimal autofluorescence interference has been wieldy applied in biosensing and bioimaging. However, the traditional emission of CL probes was mainly in the range of 400 to 650 nm, leading to undesired resolution and penetration in a biological object. Therefore, it was urgent to develop CL molecules in the near-infrared window [NIR, including NIR-I (650 to 900 nm) and near-infrared-II (900 to 1,700 nm)], coupled with unique advantages of long-time imaging, sensitive response, and high resolution at depths of millimeters. However, no NIR-II CL unimolecular probe has been reported until now. Herein, we developed an H2S-activated NIR-II CL probe [chemiluminiscence donor 950, (CD-950)] by covalently connecting two Schaap's dioxetane donors with high chemical energy to a NIR-II fluorophore acceptor candidate via intramolecular CL resonance energy transfer strategy, thereby achieving high efficiency of 95%. CD-950 exhibited superior capacity including long-duration imaging (~60 min), deeper tissue penetration (~10 mm), and specific H2S response under physiological conditions. More importantly, CD-950 showed detection capability for metformin-induced hepatotoxicity with 2.5-fold higher signal-to-background ratios than that of NIR-II fluorescence mode. The unimolecular NIR-II CL probe holds great potential for the evaluation of drug-induced side effects by tracking its metabolites in vivo, further facilitating the rational design of novel NIR-II CL-based detection platforms.

Molecular surface programming of rectifying junctions between InAs colloidal quantum dot solids.

Heavy-metal-free III-V colloidal quantum dots (CQDs) show promise in optoelectronics: Recent advancements in the synthesis of large-diameter indium arsenide (InAs) CQDs provide access to short-wave infrared (IR) wavelengths for three-dimensional ranging and imaging. In early studies, however, we were unable to achieve a rectifying photodiode using CQDs and molybdenum oxide/polymer hole transport layers, as the shallow valence bandedge (5.0 eV) was misaligned with the ionization potentials of the widely used transport layers. This occurred when increasing CQD diameter to decrease the bandgap below 1.1 eV. Here, we develop a rectifying junction among InAs CQD layers, where we use molecular surface modifiers to tune the energy levels of InAs CQDs electrostatically. Previously developed bifunctional dithiol ligands, established for II-VI and IV-VI CQDs, exhibit slow reaction kinetics with III-V surfaces, causing the exchange to fail. We study carboxylate and thiolate binding groups, united with electron-donating free end groups, that shift upward the valence bandedge of InAs CQDs, producing valence band energies as shallow as 4.8 eV. Photophysical studies combined with density functional theory show that carboxylate-based passivants participate in strong bidentate bridging with both In and As on the CQD surface. The tuned CQD layer incorporated into a photodiode structure achieves improved performance with EQE (external quantum efficiency) of 35% (>1 µm) and dark current density < 400 nA cm-2, a >25% increase in EQE and >90% reduced dark current density compared to the reference device. This work represents an advance over previous III-V CQD short-wavelength IR photodetectors (EQE < 5%, dark current > 10,000 nA cm-2).

Covariate-guided Bayesian mixture of spline experts for the analysis of multivariate high-density longitudinal data.

With rapid development of techniques to measure brain activity and structure, statistical methods for analyzing modern brain-imaging data play an important role in the advancement of science. Imaging data that measure brain function are usually multivariate high-density longitudinal data and are heterogeneous across both imaging sources and subjects, which lead to various statistical and computational challenges. In this article, we propose a group-based method to cluster a collection of multivariate high-density longitudinal data via a Bayesian mixture of smoothing splines. Our method assumes each multivariate high-density longitudinal trajectory is a mixture of multiple components with different mixing weights. Time-independent covariates are assumed to be associated with the mixture components and are incorporated via logistic weights of a mixture-of-experts model. We formulate this approach under a fully Bayesian framework using Gibbs sampling where the number of components is selected based on a deviance information criterion. The proposed method is compared to existing methods via simulation studies and is applied to a study on functional near-infrared spectroscopy, which aims to understand infant emotional reactivity and recovery from stress. The results reveal distinct patterns of brain activity, as well as associations between these patterns and selected covariates.

Lipid Landscapes: Vibrational Spectroscopy for Decoding Membrane Complexity.

Cell membranes are incredibly complex environments containing hundreds of components. Despite substantial advances in the past decade, fundamental questions related to lipid-lipid interactions and heterogeneity persist. This review explores the complexity of lipid membranes, showcasing recent advances in vibrational spectroscopy to characterize the structure, dynamics, and interactions at the membrane interface. We include an overview of modern techniques such as surface-enhanced infrared spectroscopy as a steady-state technique with single-bilayer sensitivity, two-dimensional sum-frequency generation spectroscopy, and two-dimensional infrared spectroscopy to measure time-evolving structures and dynamics with femtosecond time resolution. Furthermore, we discuss the potential of multiscale molecular dynamics (MD) simulations, focusing on recently developed simulation algorithms, which have emerged as a powerful approach to interpret complex spectra. We highlight the ongoing challenges in studying heterogeneous environments in multicomponent membranes via current vibrational spectroscopic techniques and MD simulations. Overall, this review provides an up-to-date comprehensive overview of the powerful combination of vibrational spectroscopy and simulations, which has great potential to illuminate lipid-lipid, lipid-protein, and lipid-water interactions in the intricate conformational landscape of cell membranes.

A near-infrared fluorescent probe with a substantial Stokes shift designed for the detection and imaging of ß-galactosidase within living cells and animals.

ß-Galactosidase serves as a pivotal biomarker for both cancer and cellular aging. The advancement of fluorescent sensors for tracking ß-galactosidase activity is imperative in the realm of cancer diagnosis. We have designed a near-infrared fluorescent probe (PTA-gal) for the detection of ß-galactosidase in living systems with large Stokes shifts. PTA-gal exhibits remarkable sensitivity and selectivity in detecting ß-galactosidase, producing near-infrared fluorescent signals with a remarkably low detection limit (2.2 × 10-5 U/mL) and a high quantum yield (0.30). Moreover, PTA-gal demonstrates biocompatibility and can effectively detect ß-galactosidase in cancer cells as well as within living animals.

Gender differences in the functional language networks at birth: a resting-state fNIRS study.

Numerous studies reported inconsistent results concerning gender influences on the functional organization of the brain for language in children and adults. However, data for the gender differences in the functional language networks at birth are sparse. Therefore, we investigated gender differences in resting-state functional connectivity in the language-related brain regions in newborns using functional near-infrared spectroscopy. The results revealed that female newborns demonstrated significantly stronger functional connectivities between the superior temporal gyri and middle temporal gyri, the superior temporal gyri and the Broca's area in the right hemisphere, as well as between the right superior temporal gyri and left Broca's area. Nevertheless, statistical analysis failed to reveal functional lateralization of the language-related brain areas in resting state in both groups. Together, these results suggest that the onset of language system might start earlier in females, because stronger functional connectivities in the right brain in female neonates were probably shaped by the processing of prosodic information, which mainly constitutes newborns' first experiences of speech in the womb. More exposure to segmental information after birth may lead to strengthened functional connectivities in the language system in both groups, resulting in a stronger leftward lateralization in males and a more balanced or leftward dominance in females.

Neural processing of speech comprehension in noise predicts individual age using fNIRS-based brain-behavior models.

Speech comprehension in noise depends on complex interactions between peripheral sensory and central cognitive systems. Despite having normal peripheral hearing, older adults show difficulties in speech comprehension. It remains unclear whether the brain's neural responses could indicate aging. The current study examined whether individual brain activation during speech perception in different listening environments could predict age. We applied functional near-infrared spectroscopy to 93 normal-hearing human adults (20 to 70 years old) during a sentence listening task, which contained a quiet condition and 4 different signal-to-noise ratios (SNR = 10, 5, 0, -5 dB) noisy conditions. A data-driven approach, the region-based brain-age predictive modeling was adopted. We observed a significant behavioral decrease with age under the 4 noisy conditions, but not under the quiet condition. Brain activations in SNR = 10 dB listening condition could successfully predict individual's age. Moreover, we found that the bilateral visual sensory cortex, left dorsal speech pathway, left cerebellum, right temporal-parietal junction area, right homolog Wernicke's area, and right middle temporal gyrus contributed most to prediction performance. These results demonstrate that the activations of regions about sensory-motor mapping of sound, especially in noisy conditions, could be sensitive measures for age prediction than external behavior measures.

Aerobic fitness as a moderator of acute aerobic exercise effects on executive function.

This study aimed to investigate the moderating role of aerobic fitness on the effect of acute exercise on improving executive function from both behavioral and cerebral aspects. Thirty-four young individuals with motor skills were divided into high- and low-fitness groups based on their maximal oxygen uptake. Both groups completed 30 min of moderate-intensity aerobic exercise on a power bike. Executive function tests (Flanker, N-back, More-odd-shifting) were performed before and after exercise and functional near-infrared spectroscopy was used to monitor prefrontal cerebral blood flow changes during the tasks. The results indicated significant differences between the two groups regarding executive function. Participants with lower aerobic fitness performed better than their higher fitness counterparts in inhibitory control and working memory, but not in cognitive flexibility. This finding suggests that the aerobic fitness may moderate the extent of cognitive benefits gained from acute aerobic exercise. Furthermore, the neuroimaging data indicated negative activation in the frontopolar area and dorsolateral prefrontal cortex in response to three complex tasks. These findings underscore the importance of considering individual aerobic fitness when assessing the cognitive benefits of exercise and could have significant implications for tailoring fitness programs to enhance cognitive performance.

Exploring the role of mutual prediction in inter-brain synchronization during competitive interactions: an fNIRS hyperscanning investigation.

Mutual prediction is crucial for understanding the mediation of bodily actions in social interactions. Despite this importance, limited studies have investigated neurobehavioral patterns under the mutual prediction hypothesis in natural competitive scenarios. To address this gap, our study employed functional near-infrared spectroscopy hyperscanning to examine the dynamics of real-time rock-paper-scissors games using a computerized paradigm with 54 participants. Firstly, our results revealed activations in the right inferior frontal gyrus, bilateral dorsolateral prefrontal cortex, and bilateral frontopolar cortex, each displaying distinct temporal profiles indicative of diverse cognitive processes during the task. Subsequently, a task-related increase in inter-brain synchrony was explicitly identified in the right dorsolateral prefrontal cortex, which supported the mutual prediction hypothesis across the two brains. Moreover, our investigation uncovered a close association between the coherence value in the right dorsolateral prefrontal cortex and the dynamic predictive performances of dyads using inter-subject representational similarity analysis. Finally, heightened inter-brain synchrony values were observed in the right dorsolateral prefrontal cortex before a draw compared to a no-draw scenario in the second block, suggesting that cross-brain signal patterns could be reflected in behavioral responses during competition. In summary, these findings provided initial support for expanding the understanding of cognitive processes underpinning natural competitive engagements.

Features of the speech processing network in post- and prelingually deaf cochlear implant users.

The onset of hearing loss can lead to altered brain structure and functions. However, hearing restoration may also result in distinct cortical reorganization. A differential pattern of functional remodeling was observed between post- and prelingual cochlear implant users, but it remains unclear how these speech processing networks are reorganized after cochlear implantation. To explore the impact of language acquisition and hearing restoration on speech perception in cochlear implant users, we conducted assessments of brain activation, functional connectivity, and graph theory-based analysis using functional near-infrared spectroscopy. We examined the effects of speech-in-noise stimuli on three groups: postlingual cochlear implant users (n = 12), prelingual cochlear implant users (n = 10), and age-matched individuals with hearing controls (HC) (n = 22). The activation of auditory-related areas in cochlear implant users showed a lower response compared with the HC group. Wernicke's area and Broca's area demonstrated differences network attributes in speech processing networks in post- and prelingual cochlear implant users. In addition, cochlear implant users maintain a high efficiency of the speech processing network to process speech information. Taken together, our results characterize the speech processing networks, in varying noise environments, in post- and prelingual cochlear implant users and provide new insights for theories of how implantation modes impact remodeling of the speech processing functional networks.

Functional near-infrared spectroscopy-based neurofeedback training regulates time-on-task effects and enhances sustained cognitive performance.

Time-on-task effect is a common consequence of long-term cognitive demand work, which reflects reduced behavioral performance and increases the risk of accidents. Neurofeedback is a neuromodulation method that can guide individuals to regulate their brain activity and manifest as changes in related symptoms and cognitive behaviors. This study aimed to examine the effects of functional near-infrared spectroscopy-based neurofeedback training on time-on-task effects and sustained cognitive performance. A randomized, single-blind, sham-controlled study was performed: 17 participants received feedback signals of their own dorsolateral prefrontal cortex activity (neurofeedback group), and 16 participants received feedback signals of dorsolateral prefrontal cortex activity from the neurofeedback group (sham-neurofeedback group). All participants received 5 neurofeedback training sessions and completed 2 sustained cognitive tasks, including a 2-back task and a psychomotor vigilance task, to evaluate behavioral performance changes following neurofeedback training. Results showed that neurofeedback relative to the sham-neurofeedback group exhibited increased dorsolateral prefrontal cortex activation, increased accuracy in the 2-back task, and decreased mean response time in the psychomotor vigilance task after neurofeedback training. In addition, the neurofeedback group showed slower decline performance during the sustained 2-back task after neurofeedback training compared with sham-neurofeedback group. These findings demonstrate that neurofeedback training could regulate time-on-task effects on difficult task and enhance performance on sustained cognitive tasks by increasing dorsolateral prefrontal cortex activity.

Cerebral hemodynamics underlying ankle force sense modulated by high-definition transcranial direct current stimulation.

This study aimed to investigate the effects of high-definition transcranial direct current stimulation on ankle force sense and underlying cerebral hemodynamics. Sixteen healthy adults (8 males and 8 females) were recruited in the study. Each participant received either real or sham high-definition transcranial direct current stimulation interventions in a randomly assigned order on 2 visits. An isokinetic dynamometer was used to assess the force sense of the dominant ankle; while the functional near-infrared spectroscopy was employed to monitor the hemodynamics of the sensorimotor cortex. Two-way analyses of variance with repeated measures and Pearson correlation analyses were performed. The results showed that the absolute error and root mean square error of ankle force sense dropped more after real stimulation than after sham stimulation (dropped by 23.4% vs. 14.9% for absolute error, and 20.0% vs. 10.2% for root mean square error). The supplementary motor area activation significantly increased after real high-definition transcranial direct current stimulation. The decrease in interhemispheric functional connectivity within the Brodmann's areas 6 was significantly correlated with ankle force sense improvement after real high-definition transcranial direct current stimulation. In conclusion, high-definition transcranial direct current stimulation can be used as a potential intervention for improving ankle force sense. Changes in cerebral hemodynamics could be one of the explanations for the energetic effect of high-definition transcranial direct current stimulation.

High-precision tumor resection down to few-cell level guided by NIR-IIb molecular fluorescence imaging.

In vivo fluorescence/luminescence imaging in the near-infrared-IIb (NIR-IIb, 1,500 to 1,700 nm) window under <1,000 nm excitation can afford subcentimeter imaging depth without any tissue autofluorescence, promising high-precision intraoperative navigation in the clinic. Here, we developed a compact imager for concurrent visible photographic and NIR-II (1,000 to 3,000 nm) fluorescence imaging for preclinical image-guided surgery. Biocompatible erbium-based rare-earth nanoparticles (ErNPs) with bright down-conversion luminescence in the NIR-IIb window were conjugated to TRC105 antibody for molecular imaging of CD105 angiogenesis markers in 4T1 murine breast tumors. Under a ∼940 ± 38 nm light-emitting diode (LED) excitation, NIR-IIb imaging of 1,500- to 1,700-nm emission afforded noninvasive tumor­to­normal tissue (T/NT) signal ratios of ∼40 before surgery and an ultrahigh intraoperative tumor-to-muscle (T/M) ratio of ∼300, resolving tumor margin unambiguously without interfering background signal from surrounding healthy tissues. High-resolution imaging resolved small numbers of residual cancer cells during surgery, allowing thorough and nonexcessive tumor removal at the few-cell level. NIR-IIb molecular imaging afforded 10-times-higher and 100-times-higher T/NT and T/M ratios, respectively, than imaging with IRDye800CW-TRC105 in the ∼900- to 1,300-nm range. The vastly improved resolution of tumor margin and diminished background open a paradigm of molecular imaging-guided surgery.

Chemical imaging of cellular ultrastructure by null-deflection infrared spectroscopic measurements.

Nearfield spectroscopic imaging techniques can be a powerful tool to map both cellular ultrastructure and molecular composition simultaneously but are currently limited in measurement capability. Resonance enhanced (RE) atomic force microscopy infrared (AFM-IR) spectroscopic imaging offers high-sensitivity measurements, for example, but probe-sample mechanical coupling, nonmolecular optical gradient forces, and noise overwhelm recorded chemical signals. Here, we analyze the key factors limiting AFM-IR measurements and propose an instrument design that enables high-sensitivity nanoscale IR imaging by combining null-deflection measurements with RE sensitivity. Our developed null-deflection scanning probe IR (NDIR) spectroscopic imaging provides ∼24× improvement in signal-to-noise ratio (SNR) compared with the state of the art, enables optimal signal recording by combining cantilever resonance with maximum laser power, and reduces background nonmolecular signals for improved analytical accuracy. We demonstrate the use of these properties for high-sensitivity, hyperspectral imaging of chemical domains in 100-nm-thick sections of cellular acini of a prototypical cancer model cell line, MCF-10A. NDIR chemical imaging enables facile recording of label-free, chemically accurate, high-SNR vibrational spectroscopic data from nanoscale domains, paving the path for routine studies of biomedical, forensic, and materials samples.