Chung Tin

Mechanism of augmented exercise hyperpnea in chronic heart failure and dead space loading

Patients with chronic heart failure (CHF) suffer increased alveolar VD/VT (dead-space-to-tidal-volume ratio), yet they demonstrate augmented pulmonary ventilation such that arterial [Formula: see text] ( [Formula: see text] ) remains remarkably normal from rest to moderate exercise. This paradoxical effect suggests that the control law governing exercise hyperpnea is not merely determined by metabolic CO2 production ( [Formula: see text] ) per se but is responsive to an apparent (real-feel) metabolic CO2 load ( [Formula: see text] ) that also incorporates the adverse effect of physiological VD/VT on pulmonary CO2 elimination. By contrast, healthy individuals subjected to dead space loading also experience augmented ventilation at rest and during exercise as with increased alveolar VD/VT in CHF, but the resultant response is hypercapnic instead of eucapnic, as with CO2 breathing. The ventilatory effects of dead space loading are therefore similar to those of increased alveolar VD/VT and CO2 breathing combined. These observations are consistent with the hypothesis that the increased series VD/VT in dead space loading adds to [Formula: see text] as with increased alveolar VD/VT in CHF, but this is through rebreathing of CO2 in dead space gas thus creating a virtual (illusory) airway CO2 load within each inspiration, as opposed to a true airway CO2 load during CO2 breathing that clogs the mechanism for CO2 elimination through pulmonary ventilation. Thus, the chemosensing mechanism at the respiratory controller may be responsive to putative drive signals mediated by within-breath [Formula: see text] oscillations independent of breath-to-breath fluctuations of the mean [Formula: see text] level. Skeletal muscle afferents feedback, while important for early-phase exercise cardioventilatory dynamics, appears inconsequential for late-phase exercise hyperpnea.

Self-Recalibrating Surface EMG Pattern Recognition for Neuroprosthesis Control Based on Convolutional Neural Network

Hand movement classification based on surface electromyography (sEMG) pattern recognition is a promising approach for upper limb neuroprosthetic control. However, maintaining day-to-day performance is challenged by the non-stationary nature of sEMG in real-life operation. In this study, we propose a self-recalibrating classifier that can be automatically updated to maintain a stable performance over time without the need for user retraining. Our classifier is based on convolutional neural network (CNN) using short latency dimension-reduced sEMG spectrograms as inputs. The pretrained classifier is recalibrated routinely using a corrected version of the prediction results from recent testing sessions. Our proposed system was evaluated with the NinaPro database comprising of hand movement data of 40 intact and 11 amputee subjects. Our system was able to achieve ~10.18% (intact, 50 movement types) and ~2.99% (amputee, 10 movement types) increase in classification accuracy averaged over five testing sessions with respect to the unrecalibrated classifier. When compared with a support vector machine (SVM) classifier, our CNN-based system consistently showed higher absolute performance and larger improvement as well as more efficient training. These results suggest that the proposed system can be a useful tool to facilitate long-term adoption of prosthetics for amputees in real-life applications.

Hypercapnia attenuates inspiratory amplitude and expiratory time responsiveness to hypoxia in vagotomized and vagal-intact rats

A negative influence of central chemosensitivity on peripheral chemoreflex response has been demonstrated recently in a decerebrate-vagotomized rat preparation in situ with separate carotid body and brainstem perfusions. Here, we report similar negative influences of hypercapnia on the hypoxic respiratory response in anesthetized, spontaneously breathing rats before and after vagotomy and anesthetized, artificially ventilated rats after vagotomy. Baseline breathing patterns and responsiveness to hypercapnia and hypoxia varied widely between the three respiratory modes. Despite this, the responses in inspiratory amplitude and expiratory duration (and hence respiratory frequency and neural ventilation) to hypoxia varied inversely with the background CO2 level in all three groups. Results demonstrate a hypoadditive hypercapnic-hypoxic interaction in vivo that resembles the hypoadditive central-peripheral chemoreceptor interaction in situ for these respiratory variables in the rat, regardless of differences in vagal feedback, body temperature and ventilation method. These observations stand in contrast to previous reports of hyperadditive peripheral-central chemoreceptor interaction.

Habituation without NMDA Receptor-Dependent Desensitization of Hering–Breuer Apnea Reflex in a Mecp2+/− Mutant Mouse Model of Rett Syndrome

Non-associative learning is a basic neuroadaptive behavior exhibited in almost all animal species and sensory modalities but its functions and mechanisms in the mammalian brain are poorly understood. Previous studies have identified two distinct forms of non-associative learning in the classic Hering–Breuer inflation reflex (HBIR) induced apnea in rats: NMDA receptor (NMDAR)-independent habituation in a primary vagal pathway and NMDAR-dependent desensitization in a secondary pontine pathway. Here, we show that abnormal non-associative learning of the HBIR may underlie the endophenotypic tachypnea in an animal model of Rett syndrome (RTT), an autism-spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Mecp2+/− symptomatic mice on a mixed-strain background demonstrated significantly increased resting respiratory frequency with shortened expiration and normal inspiratory duration compared with asymptomatic mutants and wild-type controls, a phenotype that is characteristic of girls with RTT. Low-intensity electrical stimulation of the vagus nerve elicited fictive HBIR with time-dependent habituation in both Mecp2+/− and wild-type mice. However, time-dependent desensitization of the HBIR was evidenced only in wild-type controls and asymptomatic mutant mice but was absent or suppressed in Mecp2+/− symptomatic mice or in wild-type mice after blockade of NMDAR with dizocilpine. Remarkably, ∼50% of the Mecp2+/− mice developed these X-linked phenotypes despite somatic mosaicism. Such RTT-like respiratory endophenotypes in mixed-strain Mecp2+/− mice differed from those previously reported in Mecp2-/y mice on pure C57BL/6J background. These findings provide the first evidence indicating that impaired NMDAR-dependent desensitization of the HBIR may contribute to the endophenotypic tachypnea in RTT.

A Reversible DNA Logic Gate Platform Operated by One- and Two-Photon Excitations.

We demonstrate the use of two different wavelength ranges of excitation light as inputs to remotely trigger the responses of the self-assembled DNA devices (D-OR). As an important feature of this device, the dependence of the readout fluorescent signals on the two external inputs, UV excitation for 1 min and/or near infrared irradiation (NIR) at 800 nm fs laser pulses, can mimic function of signal communication in OR logic gates. Their operations could be reset easily to its initial state. Furthermore, these DNA devices exhibit efficient cellular uptake, low cytotoxicity, and high bio-stability in different cell lines. They are considered as the first example of a photo-responsive DNA logic gate system, as well as a biocompatible, multi-wavelength excited system in response to UV and NIR. This is an important step to explore the concept of photo-responsive DNA-based systems as versatile tools in DNA computing, display devices, optical communication, and biology.

Use‐dependent learning and memory of the Hering–Breuer inflation reflex in rats

The classic Hering–Breuer inflation reflex (HBIR) is a widely held tenet for understanding the lung volume‐related vagal control of respiratory rhythm. Recent evidence, however, has revealed that the fictive HBIR elicited by electrical vagal stimulation in rats is not static but may be attenuated centrally by two forms of non‐associative learning (habituation and desensitization) that continually mitigate the reflex effects with exponential adaptations like a differentiator or high‐pass filter. Desensitization is analogous to habituation but exhibits an explicit short‐term memory (STM) in the form of a rebound response with exponential decay during recovery from stimulation. To investigate whether such learning and memory effects are lung volume related and use‐dependent (practice makes perfect), we compared the time‐dependent changes in inspiratory and expiratory durations (tI and tE) during and after 1 or 8 min unilateral lung inflation or high‐frequency, low‐intensity vagal stimulation in anaesthetized, uni‐ or bi‐vagotomized rats. Unilateral lung inflation and vagal stimulation both elicited abrupt shortening of tI and lengthening of tE (HBIR effects) and gradual habituation and desensitization throughout the 1 or 8 min test period, followed by rebound responses in tI and tE with exponential recovery (STM effects) in the post‐test period. In both cases, the STM time constants for tI and tE were significantly longer with the 8 min test than with the 1 min test (17–45 versus 4–11 s, P < 0.01). We conclude that the HBIR and its central habituation and desensitization are mediated peripherally by lung volume‐related vagal afferents, and that the STM of desensitization is use‐dependent. The translational implications of these findings are discussed.

Mitochondrial Delivery of Therapeutic Agents by Amphiphilic DNA Nanocarriers.

The first example of mitochondrial delivery of the anticancer drug doxorubicin (Dox) is presented by lipid-functionalized DNA nanocages (LNCs). Dox localized in mitochondria induces significant cytotoxicity and cellular apoptosis in MCF-7 compared with Dox localized in lysosomes. These results suggest that LNC has the potential to be an outstanding tool in the treatment of specific organelle-related diseases such as cancers.

Multiscale fingerprinting of neuronal functional connectivity

Current cellular-based connectomics approaches aim to delineate the functional or structural organizations of mammalian brain circuits through neuronal activity mapping and/or axonal tracing. To discern possible connectivity between functionally identified neurons in widely distributed brain circuits, reliable and efficient network-based approaches of cross-registering or cross-correlating such functional-structural data are essential. Here, a novel cross-correlation approach that exploits multiple timing-specific, response-specific, and cell-specific neuronal characteristics as coincident fingerprint markers at the systems, network, and cellular levels is proposed. Application of this multiscale temporal-cellular coincident fingerprinting assay to the respiratory central pattern generator network in rats revealed a descending excitatory pathway with characteristic activity pattern and projecting from a distinct neuronal population in pons to its counterparts in medulla that control the post-inspiratory phase of the respiratory rhythm important for normal breathing, airway protection, and respiratory-vocalization coordination. This enabling neurotracing approach may prove valuable for functional connectivity mapping of other brain circuits.

Ciguatoxin reduces regenerative capacity of axotomized peripheral neurons and delays functional recovery in pre-exposed mice after peripheral nerve injury

Ciguatera fish poisoning (CFP) results from consumption of tropical reef fish containing ciguatoxins (CTXs). Pacific (P)-CTX-1 is among the most potent known CTXs and the predominant source of CFP in the endemic region responsible for the majority of neurological symptoms in patients. Chronic and persistent neurological symptoms occur in some CFP patients, which often result in incomplete functional recovery for years. However, the direct effects of exposure to CTXs remain largely unknown. In present study, we exposed mice to CTX purified from ciguatera fish sourced from the Pacific region. P-CTX-1 was detected in peripheral nerves within hours and persisted for two months after exposure. P-CTX-1 inhibited axonal regrowth from axotomized peripheral neurons in culture. P-CTX-1 exposure reduced motor function in mice within the first two weeks of exposure before returning to baseline levels. These pre-exposed animals exhibited delayed sensory and motor functional recovery, and irreversible motor deficits after peripheral nerve injury in which formation of functional synapses was impaired. These findings are consistent with reduced muscle function, as assessed by electromyography recordings. Our study provides strong evidence that the persistence of P-CTX-1 in peripheral nerves reduces the intrinsic growth capacity of peripheral neurons, resulting in delayed functional recovery after injury.

Short latency hand movement classification based on surface EMG spectrogram with PCA

Hand gesture recognition from forearm surface electromyography (sEMG) is an active research field in the development of motor prosthesis. Studies have shown that classification accuracy and efficiency is highly dependent on the features extracted from the EMG. In this paper, we show that EMG spectrograms are a particularly effective feature for discriminating multiple classes of hand gesture when subjected to principal component analysis for dimensionality reduction. We tested our method on the Ninapro database which includes sEMG data (12 channels) of 40 subjects performing 50 different hand movements. Our results demonstrate improved classification accuracy (by ~10%) over purely time domain features for 50 different hand movements, including small finger movements and different levels of force exertion. Our method has also reduced the error rate (by ~12%) at the transition phase of gestures which could improve robustness of gesture recognition when continuous classification from sEMG is required.