Imaging nanoscale molecular binding in functionalized graphene via tip-enhanced Raman spectroscopy.

Surface functionalization of low-dimensional nanomaterials offers a means to tailor their optoelectronic and chemical characteristics. However, functionalization reactions are sensitive to the inherent surface features of nanomaterials, such as defects, grain boundaries, and edges. Conventional optical characterization methods, such as Raman spectroscopy, have limited sensitivity and spatial resolution and, therefore, struggle to visualize reaction sites and chemical species. Here, we demonstrate the capability of spatially and chemically sensitive tip-enhanced Raman spectroscopy imaging to map the distribution of molecules in covalently functionalized graphene. Hyperspectral vertex component analysis and density functional theory are necessary to interpret the nature of binding sites and extract information from the spatially and spectrally heterogeneous datasets. Our results clarify the origin of heterogeneous surface functionalization, resolving preferential binding at edges and defects. This work demonstrates the potential of nanospectroscopic tools combined with unsupervised learning to characterize complex, partially ordered optoelectronic nanomaterials.

Polyunsaturated Fatty Acids as Potential Treatments for COVID-19-Induced Anosmia.

Some individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) experience anosmia, or loss of smell. Although the prevalence of anosmia has decreased with the emergence of the Omicron variant, it remains a significant concern. This review examines the potential role of polyunsaturated fatty acids (PUFAs), particularly omega-3 PUFAs, in treating COVID-19-induced anosmia by focusing on the underlying mechanisms of the condition. Omega-3 PUFAs are known for their anti-inflammatory, neuroprotective, and neurotransmission-enhancing properties, which could potentially aid in olfactory recovery. However, study findings are inconsistent. For instance, a placebo-controlled randomized clinical trial found no significant effect of omega-3 PUFA supplementation on olfactory recovery in patients with COVID-19-induced anosmia. These mixed results highlight the limitations of existing research, including small sample sizes, lack of placebo controls, short follow-up periods, and combined treatments. Therefore, more rigorous, large-scale studies are urgently needed to definitively assess the therapeutic potential of omega-3 PUFAs for olfactory dysfunction. Further research is also crucial to explore the broader role of PUFAs in managing viral infections and promoting sensory recovery.

Biophysical mechanisms underlying tefluthrin-induced modulation of gating changes and resurgent current generation in the human Nav1.4 channel.

Human skeletal muscle contraction is triggered by activation of Nav1.4 channels. Nav1.4 channels can generate resurgent currents by channel reopening at hyperpolarized potentials through a gating transition dependent on the intracellular Navß4 peptide in the physiological conditions. Tefluthrin (TEF) is a pyrethroid insecticide that can disrupt electrical signaling in nerves and skeletal muscle, resulting in seizures, muscle spasms, fasciculations, and mental confusion. TEF can also induce tail currents through other voltage-gated sodium channels in the absence of Navß4 peptide, suggesting that muscle spasms may be caused by resurgent currents. Further, intracellular Navß4 peptide and extracellular TEF may show competitive or synergistic effects; however, their binding sites are still unknown. To address these issues, electrophysiological recordings were performed on CHO-K1 cells expressing Nav1.4 channels with intracellular Navß4 peptide, extracellular TEF, or both. TEF and Navß4 peptide induced a hyperpolarizing shift of activation and inactivation curves in the Nav1.4 channel. TEF also substantially prolonged the inactivation time constants, while simultaneous application of Navß4 peptide partially reversed this effect. Resurgent currents were enhanced by TEF and Navß4 peptide at negative potentials, but TEF more potently enhances resurgent currents and dampens decay of resurgent currents. With longer depolarization, peak resurgent currents decay was fastest with the TEF alone. Molecular docking suggested that TEF and Navß4 peptide binding site(s) are not in the narrowest part of the channel pore, but rather in the bundle-crossing regions and in the domain linkers, respectively. TEF can induce resurgent currents independently and synergistically with Navß4 peptide, which may explain the muscle spasms observed in TEF intoxication.

A multiscale ion diffusion framework sheds light on the diffusion-stability-hysteresis nexus in metal halide perovskites.

Stability and current-voltage hysteresis stand as major obstacles to the commercialization of metal halide perovskites. Both phenomena have been associated with ion migration, with anecdotal evidence that stable devices yield low hysteresis. However, the underlying mechanisms of the complex stability-hysteresis link remain elusive. Here we present a multiscale diffusion framework that describes vacancy-mediated halide diffusion in polycrystalline metal halide perovskites, differentiating fast grain boundary diffusivity from volume diffusivity that is two to four orders of magnitude slower. Our results reveal an inverse relationship between the activation energies of grain boundary and volume diffusions, such that stable metal halide perovskites exhibiting smaller volume diffusivities are associated with larger grain boundary diffusivities and reduced hysteresis. The elucidation of multiscale halide diffusion in metal halide perovskites reveals complex inner couplings between ion migration in the volume of grains versus grain boundaries, which in turn can predict the stability and hysteresis of metal halide perovskites, providing a clearer path to addressing the outstanding challenges of the field.

Prediction of in-hospital hypokalemia using machine learning and first hospitalization day records in patients with traumatic brain injury.

AIMS: Hypokalemia is a common complication following traumatic brain injury, which may complicate treatment and lead to unfavorable outcomes. Identifying patients at risk of hypokalemia on the first day of admission helps to implement prophylactic treatment, reduce complications, and improve prognosis. METHODS: This multicenter retrospective study was performed between January 2017 and December 2020 using the electronic medical records of patients admitted due to traumatic brain injury. A propensity score matching approach was adopted with a ratio of 1:1 to overcome overfitting and data imbalance during subgroup analyses. Five machine learning algorithms were applied to generate a best-performed prediction model for in-hospital hypokalemia. The internal fivefold cross-validation and external validation were performed to demonstrate the interpretability and generalizability. RESULTS: A total of 4445 TBI patients were recruited for analysis and model generation. Hypokalemia occurred in 46.55% of recruited patients and the incidences of mild, moderate, and severe hypokalemia were 32.06%, 12.69%, and 1.80%, respectively. Hypokalemia was associated with increased mortality, while severe hypokalemia cast greater impacts. The logistic regression algorithm had the best performance in predicting decreased serum potassium and moderate-to-severe hypokalemia, with an AUC of 0.73 ± 0.011 and 0.74 ± 0.019, respectively. The prediction model was further verified using two external datasets, including our previous published data and the open-assessed Medical Information Mart for Intensive Care database. Linearized calibration curves showed no statistical difference (p > 0.05) with perfect predictions. CONCLUSIONS: The occurrence of hypokalemia following traumatic brain injury can be predicted by first hospitalization day records and machine learning algorithms. The logistic regression algorithm showed an optimal predicting performance verified by both internal and external validation.

Kinetic Alterations in Resurgent Sodium Currents of Mutant Nav1.4 Channel in Two Patients Affected by Paramyotonia Congenita.

Paramyotonia congenita (PMC) is a rare skeletal muscle disorder characterized by muscle stiffness upon repetitive exercise and cold exposure. PMC was reported to be caused by dominant mutations in the SCN4A gene encoding the α subunit of the Nav1.4 channel. Recently, we identified two missense mutations of the SCN4A gene, p.V781I and p.A1737T, in two PMC families. To evaluate the changes in electrophysiological properties caused by the mutations, both mutant and wild-type (WT) SCN4A genes were expressed in CHO-K1 and HEK-293T cells. Then, whole-cell patch-clamp recording was employed to study the altered gating of mutant channels. The activation curve of transient current showed a hyperpolarizing shift in both mutant Nav1.4 channels as compared to the WT channel, whereas there was a depolarizing shift in the fast inactivation curve. These changes confer to an increase in window current in the mutant channels. Further investigations demonstrated that the mutated channel proteins generate significantly larger resurgent currents as compared to the WT channel and take longer to attain the peak of resurgent current than the WT channel. In conclusion, the current study demonstrates that p.V781I and p.A1737T mutations in the Nav1.4 channel increase both the sustained and the resurgent Na+ current, leading to membrane hyperexcitability with a lower firing threshold, which may influence the clinical phenotype.

Disease Burden Affects Aging Brain Function.

BACKGROUND: Most older adults live with multiple chronic disease conditions, yet the effect of multiple diseases on brain function remains unclear. METHODS: We examine the relationship between disease multimorbidity and brain activity using regional cerebral blood flow (rCBF) 15O-water PET scans from 97 cognitively normal participants (mean baseline age 76.5) in the Baltimore Longitudinal Study of Aging (BLSA). Multimorbidity index scores, generated from the presence of 13 health conditions, were correlated with PET data at baseline and in longitudinal change (n = 74) over 5.05 (2.74 SD) years. RESULTS: At baseline, voxel-based analysis showed that higher multimorbidity scores were associated with lower relative activity in orbitofrontal, superior frontal, temporal pole and parahippocampal regions, and greater activity in lateral temporal, occipital, and cerebellar regions. Examination of the individual health conditions comprising the index score showed hypertension and chronic kidney disease individually contributed to the overall multimorbidity pattern of altered activity. Longitudinally, both increases and decreases in activity were seen in relation to increasing multimorbidity over time. These associations were identified in orbitofrontal, lateral temporal, brainstem, and cerebellar areas. CONCLUSION: Together, these results show that greater multimorbidity is associated with widespread areas of altered brain activity, supporting a link between health and changes in aging brain function.

Extracorporeal Membrane Oxygenation for COVID-19: Case Report of Nine Patients.

Covid-19, Coronavirus disease 2019; ARDS, Acute respiratory distress syndrome; ECMO, Extracorporeal Membrane Oxygenation; WHO, World Health Organization; ICUs, Intensive care units. Acute respiratory distress syndrome (ARDS) is a fatal comorbidity of critically ill patients with COVID-19, who often end up on respiratory support. However, the safety and effectiveness of Extracorporeal Membrane Oxygenation (ECMO) in the treatment of COVID-19 remains to be elucidated at present. Here, we report on nine patients who received ECMO due to severe SARS-CoV-2 infection in Wuhan, China. Our initial experiences suggest that carefully selecting patients, as well as management by a well-trained team, are critical to implementing ECMO in patients with COVID-19. More randomized controlled trials with larger sample sizes are needed to evaluate the usefulness of ECMO in patients with COVID-19.

Cannabidiol Selectively Binds to the Voltage-Gated Sodium Channel Nav1.4 in Its Slow-Inactivated State and Inhibits Sodium Current.

Cannabidiol (CBD), one of the cannabinoids from the cannabis plant, can relieve the myotonia resulting from sodium channelopathy, which manifests as repetitive discharges of muscle membrane. We investigated the binding kinetics of CBD to Nav1.4 channels on the muscle membrane. The binding affinity of CBD to the channel was evaluated using whole-cell recording. The CDOCKER program was employed to model CBD docking onto the Nav1.4 channel to determine its binding sites. Our results revealed no differential inhibition of sodium current by CBD when the channels were in activation or fast inactivation status. However, differential inhibition was observed with a dose-dependent manner after a prolonged period of depolarization, leaving the channel in a slow-inactivated state. Moreover, CBD binds selectively to the slow-inactivated state with a significantly faster binding kinetics (>64,000 M-1 s-1) and a higher affinity (Kd of fast inactivation vs. slow-inactivation: >117.42 µM vs. 51.48 µM), compared to the fast inactivation state. Five proposed CBD binding sites in a bundle crossing region of the Nav1.4 channels pore was identified as Val793, Leu794, Phe797, and Cys759 in domain I/S6, and Ile1279 in domain II/S6. Our findings imply that CBD favorably binds to the Nav1.4 channel in its slow-inactivated state.